Heterogeneity in the Association Between the Presence of Coronary Artery Calcium and Cardiovascular Events: A Machine-Learning Approach in the MESA Study.

BACKGROUND: Coronary artery calcium (CAC) has been widely recognized as an important predictor of cardiovascular disease (CVD). Given the finite resources, it is important to identify individuals who would receive the most benefit from detecting positive CAC by screening. However, the evidence is limited as to whether the burden of positive CAC on CVD differs by multidimensional individual characteristics. We sought to investigate the heterogeneity in the association between positive CAC and incident CVD. METHODS: This cohort study included adults from MESA (Multi-Ethnic Study of Atherosclerosis) ages ≥45 years and free of cardiovascular disease. After propensity score matching in a 1:1 ratio, we applied a machine learning causal forest model to (1) evaluate the heterogeneity in the association between positive CAC and incident CVD, and (2) predict the increase in CVD risk at 10-years when CAC>0 (versus CAC=0) at the individual level. We then compared the estimated increase in CVD risk when CAC>0 to the absolute 10-year atherosclerotic CVD (ASCVD) risk calculated by the 2013 American College of Cardiology/American Heart Association pooled cohort equations. RESULTS: Across 3328 adults in our propensity score-matched analysis, our causal forest model showed the heterogeneity in the association between CAC>0 and incident CVD. We found a dose-response relationship of the estimated increase in CVD risk when CAC>0 with higher 10-year ASCVD risk. Almost all individuals (2293 of 2428 [94.4%]) with borderline risk of ASCVD or higher showed ≥2.5% increase in CVD risk when CAC>0. Even among 900 adults with low ASCVD risk, 689 (69.2%) showed ≥2.5% increase in CVD risk when CAC>0; these individuals were more likely to be male, Hispanic, and have unfavorable CVD risk factors than others. CONCLUSIONS: The expected increases in CVD risk when CAC>0 were heterogeneous across individuals. Moreover, nearly 70% of people with low ASCVD risk showed a large increase in CVD risk when CAC>0, highlighting the need for CAC screening among such low-risk individuals. Future studies are needed to assess whether targeting individuals for CAC measurements based on not only the absolute ASCVD risk but also the expected increase in CVD risk when CAC>0 improves cardiovascular outcomes.

Additive Effect of Multiple High-Risk Coronary Artery Segments on Patient Outcomes: LRP Study Sub-Analysis.

BACKGROUND: The Lipid Rich Plaque (LRP) Study established the association between high volume of lipidic content (maximum Lipid Core Burden Index [maxLCBI4mm] >400) in the coronary arteries and subsequent non-culprit major adverse cardiac events (NC-MACE). This analysis sought to assess the clinical impact of more than one lipid-rich plaque in the coronary tree. METHODS: The LRP patient population was divided into four cohorts: 1) patients with all segments with maxLCBI4mm = 0; 2) patients with all coronary segments maxLCBI4mm < 400, but >0; 3) patients with 1 segment maxLCBI4mm > 400; and 4) patients with 2+ coronary segments with maxLCBI4mm > 400. Baseline characteristics, plaque-level characteristics, and follow-up outcomes were described. RESULTS: Among 1550 patients, only 3.2 % had all segments with maxLCBI4mm = 0; 65.1 % had segments with maxLCBI4mm > 0 but <400; 22.5 % had one segment with maxLCBI4mm > 400; and 9.5 % had 2+ coronary segments with maxLCBI4mm > 400. Distribution within the coronary tree (one versus multiple arteries) did not differ. Overall, 1269 patients were allocated to follow-up (per study design). The composite of all-cause death, cardiac death, any revascularization, and NC-MACE was statistically higher in patients with 1 segment maxLCBI4mm > 400 and numerically even higher in patients with 2+ segments with maxLCBI4mm > 400. Patients with maxLCBI4mm = 0 had no events within two years. CONCLUSION: There is a stepwise increased risk of all-cause death, cardiac death, any revascularization, and NC-MACE according to the number of coronary segments with maxLCBI4mm > 400. In contrast, maxLCBI4mm = 0 results in a low event rate. CLINICAL TRIAL REGISTRATION: The Lipid-Rich Plaque Study (LRP), https://clinicaltrials.gov/ct2/show/NCT02033694, NCT02033694.

Near-Infrared Spectroscopy Intravascular-Ultrasound-Guided Intervention in Minimal Coronary Artery Stenosis: A Case Report.

Near-infrared spectroscopy intravascular ultrasounds (NIRS-IVUSs) can identify high-risk plaque morphologies associated with future event risk. However, the usage of NIRS-IVUSs is not universal. We report a case with insignificant coronary angiography (CAG) and high-risk NIRS-IVUS findings. A 58-year-old man with exertional dyspnea was admitted for a CAG evaluation. The CAG of the patient demonstrated mild angiographic stenosis in the mid-left anterior descending artery. However, NIRS-IVUS revealed a high maximum lipid core burden index at 4 mm (MaxLCBI4mm) and an intraluminal calcific protrusion with severe luminal stenosis at the lesion. Therefore, the patient was diagnosed as stable angina, and a drug-eluting stent was implanted in the lesion. A post-stent NIRS-IVUS demonstrated improved MaxLCBI4mm and significantly improved luminal stenosis. The patient did not have any procedural complications. In the present case, a patient with insignificant CAG demonstrated multiple high-risk features on NIRS-IVUS. Therefore, a percutaneous coronary intervention was performed. The presented case highlights the utility of NIRS-IVUS in nonobstructive CAG.

Performance of Coronary Artery Calcium Testing in Patients With Severe Psoriasis: Risk Assessment and Reclassification Potential in a Low Cardiovascular Risk Population / Realización del examen de calcio en los pacientes con psoriasis severa: evaluación del riesgo y potencial de reclasificación en una población de riesgo cardiovascular bajo

Background Patients with severe psoriasis have an increased cardiovascular (CV) risk and prevalence of subclinical coronary artery disease (CAD). Coronary artery calcium (CAC) testing can detect subclinical CAD and improve cardiovascular risk assessment beyond clinical scores. Objectives Evaluate the presence and magnitude of subclinical CAD determined by CAC score among the different ESC/EAS CV risk categories, as well as the potential for risk reclassification, in patients with severe psoriasis from a low CV risk population. Methods Unicentric cross-sectional study in 111 patients with severe chronic plaque psoriasis from a low CV risk population in the Mediterranean region. Patients were classified into four CV risk categories according to the ESC/EAS guideline recommendations and HeartScore/SCORE calibrated charts. Patients underwent coronary computed tomography to determine their CAC scores. Patients in the moderate-risk category with a CAC score of ≥100 were considered to be reclassified as recommended by the 2019 ESC/EAS guidelines. Reclassification was also considered for patients in the low-risk category with a CAC score>0. Results Presence of subclinical CAD was detected in 46 (41.4%) patients. These accounted for 86.2% of patients in high/very-high-risk categories and 25.6% of patients in non-high-risk categories. Fourteen (17.1%) of the patients in non-high-risk categories were reclassifiable due to their CAC score. This percentage was higher (25%) when considering the moderate-risk category alone and lower (13.8%) in the low-risk category. Age was the only variable associated with presence of subclinical CAD and reclassification. Conclusions Over 40% of patients with severe psoriasis from a low-risk region and up to 25% of those in non-high-risk categories have subclinical CAD (AU)

Antecedentes Los pacientes con psoriasis severa tienen riesgo cardiovascular (CV) incrementado, así como prevalencia de la enfermedad de las arterias coronarias (EAC) subclínica. El examen de calcio en las arterias coronarias (CAC) puede detectar la EAC subclínica y mejorar la evaluación del riesgo CV más allá de las puntuaciones clínicas. Objetivos Evaluar la presencia y magnitud de la EAC subclínica determinadas mediante la puntuación CAC entre las diferentes categorías de riesgo CV de ESC/EAS, así como el potencial de reclasificación del riesgo, en pacientes con psoriasis severa, procedentes de una población de riesgo CV bajo. Métodos Estudio transversal unicéntrico de 111 pacientes con psoriasis crónica en placa procedentes de una población de bajo riesgo CV de la región mediterránea. Los pacientes fueron clasificados en cuatro categorías de riesgo CV conforme a las recomendaciones de la guía ESC/EAS y la tabla de calibración HeartScore/SCORE. Se realizó a los pacientes una tomografía computarizada para determinar sus puntuaciones CAC. Se consideró que los pacientes de la categoría de riesgo moderado con una puntuación CAC≥100 debían ser reclasificados, conforme a las guías ESC/EAS de 2019. También se reconsideró la reclasificación para aquellos pacientes de la categoría de riesgo bajo con una puntuación CAC>0. Resultados La presencia de EAC subclínica fue detectada en 46 pacientes (41,4%), que representaron el 86,2% de los pacientes incluidos en las categorías de riesgo alto/muy alto, y el 25,6% de los pacientes de las categorías de riesgo no alto. Catorce pacientes (17,1%) de las categorías de riesgo no alto no fueron reclasificables debido a su puntuación CAC. Este porcentaje fue más alto (25%) al considerar la categoría de riesgo moderado en solitario, y más bajo (13,8%) en la categoría de riesgo bajo. La edad fue la única variable asociada a la presencia de EAC subclínica y reclasificación (AU)

[Artículo traducido] Realización del examen de calcio en los pacientes con psoriasis severa: evaluación del riesgo y potencial de reclasificación en una población de riesgo cardiovascular bajo / Performance of Coronary Artery Calcium Testing in Patients With Severe Psoriasis: Risk Assessment and Reclassification Potential in a Low Cardiovascular Risk Population

Antecedentes Los pacientes con psoriasis severa tienen riesgo cardiovascular (CV) incrementado, así como prevalencia de la enfermedad de las arterias coronarias (EAC) subclínica. El examen de calcio en las arterias coronarias (CAC) puede detectar la EAC subclínica y mejorar la evaluación del riesgo CV más allá de las puntuaciones clínicas. Objetivos Evaluar la presencia y magnitud de la EAC subclínica determinadas mediante la puntuación CAC entre las diferentes categorías de riesgo CV de ESC/EAS, así como el potencial de reclasificación del riesgo, en pacientes con psoriasis severa, procedentes de una población de riesgo CV bajo. Métodos Estudio transversal unicéntrico de 111 pacientes con psoriasis crónica en placa procedentes de una población de bajo riesgo CV de la región mediterránea. Los pacientes fueron clasificados en cuatro categorías de riesgo CV conforme a las recomendaciones de la guía ESC/EAS y la tabla de calibración HeartScore/SCORE. Se realizó a los pacientes una tomografía computarizada para determinar sus puntuaciones CAC. Se consideró que los pacientes de la categoría de riesgo moderado con una puntuación CAC≥100 debían ser reclasificados, conforme a las guías ESC/EAS de 2019. También se reconsideró la reclasificación para aquellos pacientes de la categoría de riesgo bajo con una puntuación CAC>0. Resultados La presencia de EAC subclínica fue detectada en 46 pacientes (41,4%), que representaron el 86,2% de los pacientes incluidos en las categorías de riesgo alto/muy alto, y el 25,6% de los pacientes de las categorías de riesgo no alto. Catorce pacientes (17,1%) de las categorías de riesgo no alto no fueron reclasificables debido a su puntuación CAC. Este porcentaje fue más alto (25%) al considerar la categoría de riesgo moderado en solitario, y más bajo (13,8%) en la categoría de riesgo bajo. La edad fue la única variable asociada a la presencia de EAC subclínica y reclasificación (AU)

Background Patients with severe psoriasis have an increased cardiovascular (CV) risk and prevalence of subclinical coronary artery disease (CAD). Coronary artery calcium (CAC) testing can detect subclinical CAD and improve cardiovascular risk assessment beyond clinical scores. Objectives Evaluate the presence and magnitude of subclinical CAD determined by CAC score among the different ESC/EAS CV risk categories, as well as the potential for risk reclassification, in patients with severe psoriasis from a low CV risk population. Methods Unicentric cross-sectional study in 111 patients with severe chronic plaque psoriasis from a low CV risk population in the Mediterranean region. Patients were classified into four CV risk categories according to the ESC/EAS guideline recommendations and HeartScore/SCORE calibrated charts. Patients underwent coronary computed tomography to determine their CAC scores. Patients in the moderate-risk category with a CAC score of ≥100 were considered to be reclassified as recommended by the 2019 ESC/EAS guidelines. Reclassification was also considered for patients in the low-risk category with a CAC score>0. Results Presence of subclinical CAD was detected in 46 (41.4%) patients. These accounted for 86.2% of patients in high/very-high-risk categories and 25.6% of patients in non-high-risk categories. Fourteen (17.1%) of the patients in non-high-risk categories were reclassifiable due to their CAC score. This percentage was higher (25%) when considering the moderate-risk category alone and lower (13.8%) in the low-risk category. Age was the only variable associated with presence of subclinical CAD and reclassification. Conclusions Over 40% of patients with severe psoriasis from a low-risk region and up to 25% of those in non-high-risk categories have subclinical CAD (AU)

Influence of myocardial bridge on atherosclerotic plaque distribution and characteristics evaluated by near-infrared spectroscopy intravascular ultrasound.

BACKGROUND: This study aims to clarify whether myocardial bridge (MB) could influence atherosclerotic plaque characteristics assessed using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) imaging. METHODS: One hundred and sixteen patients who underwent percutaneous coronary intervention (PCI) using NIRS-IVUS imaging were included. MB was defined as an echo-lucent band surrounding left anterior descending artery (LAD). In MB patients, LAD was divided into three segments: proximal, MB, and distal segments. In non-MB patients, corresponding three segments were defined based on the average length of the above segments. Segmental maximum plaque burden and lipid content derived from NIRS-IVUS imaging in the section of maximum plaque burden were evaluated in each segment. Lipid content of atherosclerotic plaque was evaluated as lipid core burden index (LCBI) and maxLCBI4mm. LCBI is the fraction of pixels indicating lipid within a region multiplied by 1000, and the maximum LCBI in any 4-mm region was defined as maxLCBI4mm. RESULTS: MB was identified in 42 patients. MB was not associated with maximum plaque burden in proximal segment. LCBI and maxLCBI4mm were significantly lower in patients with MB than those without in proximal segment. Multivariable analysis demonstrated both MB and maximum plaque burden in proximal segment to be independent predictors of LCBI in proximal segment. CONCLUSIONS: Lipid content of atherosclerotic plaque assessed by NIRS-IVUS imaging was significantly smaller in patients with MB than those without. MB could be considered as a predictor of lipid content of atherosclerotic plaque when assessed by NIRS-IVUS imaging.

Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. METHODS: We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes. RESULTS: We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33). CONCLUSIONS: Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

Accumulation of Plasma-Derived Lipids in the Lipid Core and Necrotic Core of Human Atheroma: Imaging Mass Spectrometry and Histopathological Analyses.

Objective: To clarify the pathogenesis of human atheroma, the origin of deposited lipids, the developmental mechanism of liponecrotic tissue, and the significance of the oxidation of phospholipids were investigated using mass spectrometry-aided imaging and immunohistochemistry.Atherosclerotic lesions in human coronary arteries were divided into 3 groups: pathologic intimal thickening with lipid pool, atheroma with lipid core, and atheroma with necrotic core. The lipid pool and lipid core were characterized by the deposition of extracellular lipids. The necrotic core comprised extracellular lipids and liponecrotic tissue. The proportion of cholesteryl linoleate in cholesteryl linoleate+cholesteryl oleate fraction in the extracellular lipid and liponecrotic regions differed significantly from that of the macrophage foam cell-dominant region, and the plasma-derived components (apolipoprotein B and fibrinogen) were localized in the regions. The liponecrotic region was devoid of elastic and collagen fibers and accompanied by macrophage infiltration in the surrounding tissue. Non-oxidized phospholipid (Non-OxPL), OxPL, and Mox macrophages were detected in the three lesions. In the atheroma with lipid core and atheroma with necrotic core, non-OxPL tended to localize in the superficial layer, whereas OxPL was distributed evenly. Mox macrophages were colocalized with OxPL epitopes.In human atherosclerosis, plasma-derived lipids accumulate to form the lipid pool of pathologic intimal thickening, lipid core of atheroma with lipid core, and necrotic core of atheroma with necrotic core. The liponecrotic tissue in the necrotic core appears to be developed by the loss of elastic and collagen fibers. Non-OxPL in the accumulated lipids is oxidized to form OxPL, which may contribute to the lesion development through Mox macrophages.

Expression Profile of Genes Encoding Proteins Involved in Regulation of Vasculature Development and Heart Muscle Morphogenesis-A Transcriptomic Approach Based on a Porcine Model.

Despite significant advances in treatment of acute coronary syndromes (ACS) many subjects still develop heart failure due to significantly reduced ejection fraction. Currently, there are no commonly available treatment strategies that replace the infarcted/dysfunctional myocardium. Therefore, understanding the mechanisms that control the regeneration of the heart muscle is important. The development of new coronary vessels plays a pivotal role in cardiac regeneration. Employing microarray expression assays and RT-qPCR validation expression pattern of genes in long-term primary cultured cells isolated form the right atrial appendage (RAA) and right atrium (RA) was evaluated. After using DAVID software, it indicated the analysis expression profiles of genes involved in ontological groups such as: "angiogenesis", "blood vessel morphogenesis", "circulatory system development", "regulation of vasculature development", and "vasculature development" associated with the process of creation new blood vessels. The performed transcriptomic comparative analysis between two different compartments of the heart muscle allowed us to indicate the presence of differences in the expression of key transcripts depending on the cell source. Increases in culture intervals significantly increased expression of SFRP2, PRRX1 genes and some other genes involved in inflammatory process, such as: CCL2, IL6, and ROBO1. Moreover, the right atrial appendage gene encoding lysyl oxidase (LOX) showed much higher expression compared to the pre-cultivation state.

Research on the correlation between activating transcription factor 3 expression in the human coronary artery and atherosclerotic plaque stability.

BACKGROUND: Activating transcription factor 3 (ATF3) is an early response gene that is activated in response to atherosclerotic stimulation and may be an important factor in inhibiting the progression of atherosclerosis. In this study, we directly measured the expression of ATF3 and inflammatory factors in human coronary atherosclerotic plaques to examine the relationship between ATF3 expression, inflammation and structural stability in human coronary atherosclerotic plaques. METHODS: A total of 68 coronary artery specimens were collected from the autopsy group, including 36 cases of sudden death from coronary heart disease (SCD group) and 32 cases of acute death caused by mechanical injury with coronary atherosclerosis (CHD group). Twenty-two patients who had no coronary heart disease were collected as the control group (Con group). The histological structure of the coronary artery was observed under a light microscope after routine HE staining, and the intimal and lesion thicknesses, thickness of the fibrous cap, thickness of necrosis core, degree of lumen stenosis were assessed by image analysis software. Western blotting and immunohistochemistry were used to measure the expression and distribution of ATF3, inflammatory factors (CD45, IL-1ß, TNF-α) and matrix metalloproteinase-9 (MMP-9) and vascular cell adhesion molecule 1 (VCAM1) in the coronary artery. The Pearson correlation coefficient was used to analyse the correlation between ATF3 protein expression and inflammatory factors and between ATF3 protein expression and structure-related indexes in the lesion group. RESULTS: Compared with those in the control group, the intima and necrotic core in the coronary artery were thickened, the fibrous cap became thin and the degree of vascular stenosis was increased in the lesion group, while the intima and necrotic core became thicker and the fibrous cap became thinner in the SCD group than in the CHD group (P < 0.05). There was no or low expression of ATF3, inflammatory factors, VCAM1 and MMP-9 in the control group, and the expression of inflammatory factors, VCAM1 and MMP-9 in the SCD group was higher than that in CHD group, while the expression of ATF3 in the SCD group was significantly lower than that in CHD group (P < 0.05). In the lesion group, the expression of ATF3 was negatively correlated with intimal and necrotic focus thickness, positively correlated with fibrous cap thickness (P < 0.01), and negatively correlated with inflammatory factors, VCAM1 and MMP-9 (P < 0.01). CONCLUSIONS: The expression of ATF3 may be related to the progression and stability of atherosclerotic plaques, and may affect the structural stability of atherosclerotic plaques by regulating the inflammatory response, thus participating in the regulation of atherosclerotic progression.

Cardiotoxicity of Radiation Therapy: Mechanisms, Management, and Mitigation.

OPINION STATEMENT: Radiation therapy is a key component of modern-day cancer therapy and can reduce the rates of recurrence and death from cancer. However, it can increase risk of cardiovascular (CV) events, and our understanding of the timeline associated with that risk is shorter than previously thought. Risk mitigation strategies, such as different positioning techniques, and breath hold acquisitions as well as baseline cardiovascular risk stratification that can be undertaken at the time of radiotherapy planning should be implemented, particularly for patients receiving chest radiation therapy. Primary and secondary prevention of cardiovascular disease (CVD), as appropriate, should be used before, during, and after radiation treatment in order to minimize the risks. Opportunistic screening for subclinical coronary disease provides an attractive possibility for primary/secondary CVD prevention and thus mitigation of long-term CV risk. More data on long-term clinical usefulness of this strategy and development of appropriate management pathways would further strengthen the evidence for the implementation of such screening. Clear guidelines in initial cardiovascular screening and cardiac aftercare following radiotherapy need to be formulated in order to integrate these measures into everyday clinical practice and policy and subsequently improve post-treatment morbidity and mortality for these patients.

Role of coronary artery calcium score in the primary prevention of cardiovascular disease.

First developed in 1990, the Agatston coronary artery calcium (CAC) score is an international guideline-endorsed decision aid for further risk assessment and personalized management in the primary prevention of atherosclerotic cardiovascular disease. This review discusses key international studies that have informed this 30 year journey, from an initial coronary plaque screening paradigm to its current role informing personalized shared decision making. Special attention is paid to the prognostic value of a CAC score of zero (the so called "power of zero"), which, in a context of low estimated risk thresholds for the consideration of preventive therapy with statins in current guidelines, may be used to de-risk individuals and thereby inform the safe delay or avoidance of certain preventive therapies. We also evaluate current recommendations for CAC scoring in clinical practice guidelines around the world, and past and prevailing barriers for its use in routine patient care. Finally, we discuss emerging approaches in this field, with a focus on the potential role of CAC informing not only the personalized allocation of statins and aspirin in the general population, but also of other risk-reduction therapies in special populations, such as individuals with diabetes and people with severe hypercholesterolemia.

Cardiovascular risk assessment by coronary artery calcium score in subjects with maturity-onset diabetes of the young caused by glucokinase mutations.

AIMS: Maturity-Onset Diabetes of the Young (MODY) caused by glucokinase (GCK) mutations is characterized by lifelong mild non-progressive hyperglycemia, with low frequency of coronary artery disease (CAD) compared to other types of diabetes. The aim of this study is to estimate cardiovascular risk by coronary artery calcification (CAC) score in this group. MATERIALS AND METHODS: Twenty-nine GCK-MODY cases, 26 normoglycemic controls (recruited among non-affected relatives/spouses of GCK mutation carriers), and 24 unrelated individuals with type 2 diabetes were studied. Patients underwent CAC score evaluation by computed tomography and were classified by Agatston score ≥ or < 10. Framingham Risk scores of CAD in 10 years were calculated. RESULTS: Median [interquartile range] CAC score in GCK-MODY was 0 [0,0], similar to controls (0 [0,0], P = 0.49), but lower than type 2 diabetes (39 [0, 126], P = 2.6 × 10-5). A CAC score ≥ 10 was seen in 6.9% of the GCK group, 7.7% of Controls (P = 1.0), and 54.2% of individuals with type 2 diabetes (P = 0.0006). Median Framingham risk score was lower in GCK than type 2 diabetes (3% vs. 13%, P = 4 × 10-6), but similar to controls (3% vs. 4%, P = 0.66). CONCLUSIONS: CAC score in GCK-MODY is similar to control individuals from the same family and/or household and is significantly lower than type 2 diabetes. Besides demonstrating low risk of CAD in GCK-MODY, these findings may contribute to understanding the specific effect of hyperglycemia in CAD.

In vitro and in vivo evaluation of a novel bioresorbable magnesium scaffold with different surface modifications.

The novel Resoloy® rare earth magnesium alloy was developed for bioresorbable vascular implant application, as an alternative to the WE43 used in Biotronik's Magmaris scaffold, which received CE approval in 2016. Initially, the Magmaris showed very promising preclinical and clinical results, but the formation of an unexpected conversion product and a too fast loss of integrity has proven to be a flaw. The safety and efficacy of Resoloy, which is intended to be bioresorbed without any remnants, has been investigated in an in vitro degradation study and a porcine coronary animal model. Four different groups of scaffolds composed of Resoloy (Res) as the backbone material and additionally equipped with a fluoride passivation layer (Res-F), a polyester topcoat (Res-P), or a duplex layer composed of a fluoride passivation layer and a polymeric topcoat (Res-PF) were compared to a Magmaris scaffold in an in vitro degradation test. Preclinical safety and efficacy of Res-F and Res-PF were subsequently evaluated in a coronary porcine model for 12 and 28 days. Scanning electron microscope, quantitative coronary angiography, micro-computed tomography, histopathology, and histomorphometry analyses were conducted to evaluate preclinical parameters and degradation behavior of the scaffolds. Res-PF with a duplex layer shows the slowest degradation and the longest supporting force of all test groups. The in vitro data are confirmed by the results of the in vivo study, in which Res-PF exhibited a longer supporting force than Res-F, but also caused higher neointima formation. Both studied groups showed excellent biocompatibility. A starter colonization of the strut area with cells during bioresorption was observed. The in vitro degradation test shows that a combination of MgF2 passivation and a PLLA topcoat on a Resoloy magnesium backbone (Res-PF) leads to a much slower degradation and a longer support time than a Magmaris control group. In a preclinical study, the safety and efficacy of this duplex layer could be demonstrated. The beginning colonization of the degraded strut area by macrophages can be seen as clear indications that the resorption of the intermediate degradation product takes a different course than that of the Magmaris scaffold.

Development and Validation of a Bioanalytical LC-MS/MS Method for Simultaneous Determination of Sirolimus in Porcine Whole Blood and Lung Tissue and Pharmacokinetic Application with Coronary Stents.

Sirolimus is a hydrophobic macrolide compound that has been used for long-term immunosuppressive therapy, prevention of restenosis, and treatment of lymphangioleiomyomatosis. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of sirolimus in both porcine whole blood and lung tissue. Blood and lung tissue homogenates were deproteinized with acetonitrile and injected into the LC-MS/MS system for analysis using the positive electrospray ionization mode. The drug was separated on a C18 reversed phase column with a gradient mobile phase (ammonium formate buffer (5 mM) with 0.1% formic acid and acetonitrile) at 0.2 mL/min. The selected reaction monitoring transitions of m/z 931.5 → 864.4 and m/z 809.5 → 756.5 were applied for sirolimus and ascomycin (the internal standard, IS), respectively. The method was selective and linear over a concentration range of 0.5-50 ng/mL. The method was validated for sensitivity, accuracy, precision, extraction recovery, matrix effect, and stability in porcine whole blood and lung tissue homogenates, and all values were within acceptable ranges. The method was applied to a pharmacokinetic study to quantitate sirolimus levels in porcine blood and its distribution in lung tissue following the application of stents in the porcine coronary arteries. It enabled the quantification of sirolimus concentration until 2 and 14 days in blood and in lung tissue, respectively. This method would be appropriate for both routine porcine pharmacokinetic and bio-distribution studies of sirolimus formulations.

Cardiovascular and All-Cause Mortality Risk by Coronary Artery Calcium Scores and Percentiles Among Older Adult Males and Females.

BACKGROUND: Coronary calcium is a marker of coronary atherosclerosis and established predictor of cardiovascular risk in general populations; however, there are limited studies examining its prognostic value among older adults (≥75 years) and even less regarding its utility in older males compared with females. Accordingly, we sought to examine the prognostic significance of both absolute and percentile coronary calcium scores among older adults. METHODS: The multicenter Coronary Artery Calcium Consortium consists of 66,636 asymptomatic patients without cardiovascular disease. Participants ages ≥75 were included in this study and stratified by sex. Multivariable Cox regression models were constructed to assess cardiovascular and all-cause mortality risk by Agatston coronary calcium scores and percentiles. RESULTS: Among 2,474 asymptomatic patients (mean age 79 years, 10.4-year follow-up), prevalence of coronary artery calcium was 92%. For both sexes, but in females more so than males, higher coronary calcium score and percentiles were associated with increased cardiovascular and all-cause mortality risk. Those at the lowest coronary calcium categories (0-9 and <25 percentile) had significantly lower risk of cardiovascular and all-cause mortality relative to the rest of the population. Multivariable analyses of traditional cardiovascular risk factors and coronary artery calcium variables revealed that age and coronary calcium were the strongest independent predictors for adverse outcomes. CONCLUSIONS: Both coronary artery calcium scores and percentiles are strongly predictive of cardiovascular and all-cause mortality among older adults, with greater risk-stratification among females than males. Both low coronary artery calcium scores 0-9 and <25th percentile define relatively low risk older adults.