Artery Calcium Research Articles

Arterial calcification volume is associated with a higher risk of cardiovascular events in pseudoxanthoma elasticum

Background and aims– Pseudoxanthoma elasticum (PXE) patients have more arterial calcification due to lower levels of inorganic pyrophosphate, caused by mutations in the ABCC6 gene, but the relation with vascular complications is poorly understood. Because of the slow progressing nature of arterial disease in PXE patients, there is a need for a valid and reliable intermediate endpoint to be used in future clinical trials. Arterial calcification measured on computed tomography (CT) is a promising candidate, if associated with future cardiovascular events. We aimed to establish the relation between arterial calcification measured on CT and future cardiovascular events in patients with PXE. Methods– In this prospective cohort study, patients with PXE from the Dutch UMC Utrecht Expertise Center for PXE (UECP) were included. Arterial calcification volume was measured on low dose full body CT scans. Patient were followed for incident cardiovascular events. The relation between arterial calcification and the risk of cardiovascular events was analyzed using Cox proportional hazard models. Results– In 326 patients (median follow-up 6.0, IQR 3.8 – 8.2 years) 41 cardiovascular events were observed (21 events per 1000 person years). In patients with no cardiovascular history, there was a significant relation between the log arterial calcification volume at baseline and future cardiovascular events (adjusted HR: 1.87, 95% CI: 1.14 – 3.09, per 1 log unit increase in arterial calcification). There was no relation in patients with clinical manifest cardiovascular disease at baseline between arterial calcification volume and future cardiovascular events. Conclusions– Higher arterial calcification volumes on CT in PXE patients are associated with a higher risk of a first cardiovascular event. This cohort study suggests that arterial calcification can be used as an intermediate endpoint in studies evaluating interventions to lower the risk of cardiovascular events.

Phosphate overload via the type III Na-dependent Pi transporter represses aortic wall elastic fiber formation.

Phosphate (Pi) induces differentiation of arterial smooth muscle cells to the osteoblastic phenotype by inducing the type III Na-dependent Pi transporter Pit-1/solute carrier family member 1. This induction can contribute to arterial calcification, but precisely how Pi stress acts on the vascular wall remains unclear. We investigated the role of extracellular Pi in inducing microstructural changes in the arterial wall. Aortae of Pit-1-overexpressing transgenic (TG) rats and their wild-type (WT) littermates were obtained at 8 weeks after birth. The thoracic descending aorta from WT and TG rats was used for the measurement of wall thickness and uniaxial tensile testing. Structural and ultrastructural analyses were performed using light microscopy and transmission electron microscopy. Gene expression of connective tissue components in the aorta was quantified by quantitative real-time polymerase chain reaction. Aortic wall thickness in TG rats was the same as that in WT rats. Uniaxial tensile testing showed that the circumferential breaking stress in TG rats was significantly lower than that in WT rats (p<0.05), although the longitudinal breaking stress, breaking strain, and elastic moduli in both directions in TG rats were unchanged. Transmission electron microscopy analysis of the aorta from TG rats showed damaged formation of elastic fibers in the aortic wall. Fibrillin-1 gene expression levels in the aorta were significantly lower in TG rats than in WT rats (p<0.05). Pi overload acting via the arterial wall Pit-1 transporter weakens circumferential strength by causing elastic fiber malformation, probably via decreased fibrillin-1 expression.

Can Artificial Intelligence Help Us in the Evaluation of Coronary Artery Calcification Scores by Acting as a Prognosticator in Patients That Are Operated on Due to Non-Small Cell Lung Cancer? A Pivotal Study

Background: Non-small cell lung cancer (NSCLC) is the leading cause of death from malignancies, and surgical resection is the most effective form of treatment. Coronary artery disease (CAD) is a common comorbidity in patients with NSCLC. A coronary artery calcium (CAC) score correlates with the extent of CAD. We aimed to test whether an automated assessment of CAC scores helps to identify the population of patients with a higher risk of postoperative complications and worse overall survival (OS) after the surgical treatment of NSCLC. Methods: In this retrospective cohort study, the data of the patients who were surgically treated for NSCLC were matched with the reassessed preoperative CT images. The postoperative complication rates and overall survival were analyzed. The CAC score was evaluated automatically using the Syngo.via Siemens Healthcare software. Cardiac age was assessed according to Hoff et al. 2001. The prognosticators of postoperative complications and of OS were tested. Results: The data of 193 patients with complete data, an adherence to the inclusion and exclusion criteria, and that were operated between 2018 and 2019, were included. Cardiac age was a predictor of the cardiovascular and pulmonary complications rate (95%CI −0.007–0.203, p = 0.066, beta coefficient 0.098). In a multivariable stepwise regression analysis, operative access was a predictor of cardiovascular and pulmonary complications (95%CI −0.290–−0.111, p &lt; 0.001, beta coefficient −0.200), cardiovascular complications (95%CI −0.161–−0.022, p = 0.011, beta coefficient −0.036), and the general complication rate (95%CI −0.370–−0.194, p &lt; 0.001, beta coefficient −0.286). Kaplan–Meier curves were separated in the survival analysis of groups of patients with a cardiac age 0–69 years vs. an age of 70+ (92 vs. 92 patients) (in Cox regression analysis, HR = 1.678, 95%CI 0.847–3.292 p = 0.138). Conclusions: An automated CAC score assessment may be a potential and clinically meaningful prognosticator of both postoperative complications and OS in patients that are operated on due to NSCLC. Further studies are required.

Exploring the Relationship Between Visceral Fat and Coronary Artery Calcification Risk Using Metabolic Score for Visceral Fat (METS-VF)

Background: Metabolic Score for Visceral Fat (METS-VF) is a novel indicator for estimating intra-abdominal fat, yet its connection with coronary artery calcification (CAC) remains uncharted. Our research aims to explore the novel METS-VF indicator’s link to CAC while comparing its performance against relevant anthropometric indices. Methods: This study enrolled participants who underwent health checkups and computed tomography scans for categorizing severity of CAC using the coronary artery calcium score. The METS-VF was calculated and compared with anthropometric indices in estimating the presence of CAC and different CAC severity using receiver operating characteristic curves. Results: Overall, 1217 participants (mean age 50.7 ± 9.9, 53.8% male) were included. METS-VF (odds ratio [OR], 1.506; 95% confidence interval [CI], 1.181–1.921; p = 0.001) was positively associated with the presence of CAC, even after accounting for cardiometabolic factors. Notably, METS-VF was positively associated with mild (OR, 1.450; 95% CI, 1.115–1.886; p = 0.006), moderate (OR, 1.865; 95% CI, 1.137–3.062; p = 0.014), and severe (OR, 2.316; 95% CI, 1.090–4.923; p = 0.029) CAC. Moreover, METS-VF yielded the highest area under curve (AUC) value in the estimation of the CAC presence (AUC = 0.710), mild (AUC = 0.682), moderate (AUC = 0.757), and severe (AUC = 0.807) CAC when compared with body mass index, waist circumference, visceral adiposity index, triglyceride–glucose index, and metabolic score for insulin resistance. The optimal METS-VF cut-off value was 6.4 for predicting CAC. Conclusions: METS-VF emerged as a strong independent marker for detecting CAC presence across mild, moderate, and severe CAC categories, outperforming major anthropometric indices in accurately estimating the presence of CAC and different severity of CAC.

The Paradox of Physical Activity and Coronary Artery Calcification: Implications for Cardiovascular Risk

The introduction of CT scans and the subsequent Agatston score in the 1990s drastically improved our ability to detect coronary artery calcification (CAC). This led to its incorporation into cardiovascular risk assessment guidelines set forth by organizations such as the American Heart Association (AHA) and the American College of Cardiology (ACC). Over time, these guidelines have evolved significantly, reflecting an increasing understanding of CAC. Physical activity has become a key factor in the management of cardiovascular disease. However, the relationship between physical activity and CAC remains complex. Although physical activity is generally beneficial for cardiovascular health, paradoxically, high levels of physical activity have been associated with elevated CAC scores. However, these higher CAC levels may indicate the presence of more stable, calcified plaques that provide protection against plaque rupture. These contradictory findings call for balanced interpretations that acknowledge the cardiovascular benefits of physical activity. This review examines the historical development of clinical guidelines for CAC, the paradoxical relationship between physical activity and CAC, and potential underlying mechanisms. It emphasizes the need for future research to utilize objective measures and consistent methodologies to better understand the relationship between physical activity and CAC.

Characteristics and outcomes of patients with stent implantation for coronary artery lesions caused by Kawasaki disease - insights from second-generation stent implantation.

Adult Kawasaki patients may require intervention for occlusive coronary artery disease. Some adverse effects of first-generation drug-eluting stent implantation with sirolimus have been reported in this population. A total of nine lesions in eight (seven males, one female) patients who underwent stent implantations in this population between 2000 and 2021 were reviewed. The age at stent implantation ranged from 31 to 47 years, with a median of 37 years. There were six lesions treated by primary percutaneous transluminal coronary interventions, and three by elective procedures. A coronary aneurysm was found in two lesions, and coronary artery calcification was found in all culprit lesions. The numbers of everolimus-eluting stents, sirolimus-eluting stents and bare metal stents were six, two, and one, respectively. As anti- thrombotic therapy, aspirin, clopidogrel, and prasugrel were given to four, three, and one, respectively. Warfarin was given to five patients. The follow-up ranged from 2 to 12 years, with a median of 4 years. Follow-up angiograms were performed for eight lesions, at 2 to 38 months, with a median of 11 months. The patency of the target vessel was confirmed in all eight vessels. Slight malapposition, and peri-stent contrast staining were found in two lesions each. Acute coronary syndrome due to coronary artery lesions caused by Kawasaki disease occurred, even in lesions without any apparent coronary artery aneurysms. In our study, we show safe and efficacious placement of second-generation stent without adverse effects during the short-term follow-up, but long-term follow-up is needed to determine the efficacy and complication.

Assessment of Cutting-Balloon Angioplasty with Novel Bioabsorbable Polymer-Coated Everolimus-Eluting Stent in Treating Calcified Coronary Lesions Guided by Intravascular Ultrasound (CUPID Trial): study design and protocol

BackgroundVarious devices and techniques have been used for plaque modification in the treatment of severe coronary artery calcification. This prospective, multicenter, randomized, open-label study aims to evaluate the safety and efficacy of cutting balloon angioplasty using a novel bioabsorbable polymer-coated everolimus-eluting coronary stent for treating various degrees of calcified coronary lesions.MethodsWe outline the trial design aimed at assessing whether the cutting balloon (Wolverine™) is non-inferior to the non-compliant balloon in treating patients with calcified lesions, encompassing both de novo and in-stent restenosis (ISR) lesions. We aim to enroll 250 patients who have undergone bioabsorbable polymer-coated everolimus-eluting coronary stent (Synergy™) implantation. The primary endpoint is the minimal stent cross-sectional area at the calcium site as determined by intravascular ultrasonography. The secondary endpoints include major adverse cardiac events and target lesion revascularization at 12 months, alongside procedural convenience and operator-centric parameters, such as the number of balloons used, procedure time, and total contrast medium volume used.DiscussionIn this study, we will evaluate the efficacy and safety of Wolverine™ and non-compliant balloon in patients with calcified coronary lesions and provide a rationale for which type of balloons will optimally modify calcium lesions. In addition, we will attempt to expand the indications of the cutting balloon for treating mild-to-severe calcified coronary lesions. As the scope of insurance coverage for cutting balloons remains limited in some countries, this study may provide evidence for extending insurance coverage to the treatment of de novo calcified and ISR lesions.Trial registrationClinicalTrials.gov NCT06177808. Registered on January 1, 2024.

Artificial Intelligence-based Software for Breast Arterial Calcification Detection on Mammograms.

The performance of a commercially available artificial intelligence (AI)-based software that detects breast arterial calcifications (BACs) on mammograms is presented. This retrospective study was exempt from IRB approval and adhered to the HIPAA regulations. Breast arterial calcification detection using AI was assessed in 253 patients who underwent 314 digital mammography (DM) examinations and 143 patients who underwent 277 digital breast tomosynthesis (DBT) examinations between October 2004 and September 2022. Artificial intelligence performance for binary BAC detection was compared with ground truth (GT) determined by the majority consensus of breast imaging radiologists. Area under the receiver operating curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value (NPV), accuracy, and BAC prevalence rates of the AI algorithm were compared. The case-level AUCs of AI were 0.96 (0.93-0.98) for DM and 0.95 (0.92-0.98) for DBT. Sensitivity, specificity, and accuracy were 87% (79%-93%), 92% (88%-96%), and 91% (87%-94%) for DM and 88% (80%-94%), 90% (84%-94%), and 89% (85%-92%) for DBT. Positive predictive value and NPV were 82% (72%-89%) and 95% (92%-97%) for DM and 84% (76%-90%) and 92% (88%-96%) for DBT, respectively. Results are 95% confidence intervals. Breast arterial calcification prevalence was similar for both AI and GT assessments. Breast AI software for detection of BAC presence on mammograms showed promising performance for both DM and DBT examinations. Artificial intelligence has potential to aid radiologists in detection and reporting of BAC on mammograms, which is a known cardiovascular risk marker specific to women.

Evolving use and clinical outcomes of coronary intravascular lithotripsy: insights from an international, multicentre registry

BackgroundIntravascular lithotripsy (IVL) is increasingly used for treatment of coronary artery calcification. This study aimed to evaluate contemporary utilisation patterns, safety and efficacy of IVL in an unselected real-world patient cohort.MethodsWe included 454 patients undergoing IVL from May 2019 to February 2024 across seven centres in two European countries. Key endpoints included device success, technical success, procedural success, IVL-related complications and major adverse cardiovascular events (MACE) at 1-year follow-up.ResultsThe cohort (mean age 73±9 years, 75% male) had a mean SYNTAX Score of 22.0±13.6. Device, technical and procedural success were achieved in 98%, 91% and 89% of patients, respectively. IVL-related complications occurred in six patients (1%). At 1-year follow-up, MACE was observed in 37 patients (13%). Over time, IVL use increased in patients with acute coronary syndrome (p=0.004) and in combination with intracoronary imaging (p=0.002), while use of other calcium modification devices decreased (p=0.034).ConclusionIn this real-world registry, IVL demonstrated efficacy across diverse clinical and anatomical settings. High success rates, low complication rates and MACE rates were observed acutely and at 1-year follow-up. Utilisation patterns evolved over time, with increased adoption in acute scenarios and alongside intracoronary imaging.

Progress in understanding the genetic underpinning of coronary artery disease: from genotype to phenotype

Abstract Background The functional dissection of genetic risk opens the door to strategies for pharmacological manipulation of molecular and cellular processes implicated in human diseases, including coronary artery disease (CAD). Aim To assess the relationship between a set of single nucleotide polymorphisms previously associated with CAD and coronary artery calcium (CAC) score in an asymptomatic population from Portugal. Methods Prospective study in a cohort of 1,284 subjects aged 59.3±8.9 years, 73.6% males without apparent CAD. The CAC score was performed by cardiac computed tomography and reported as Agatston units according to the Hoff nomogram. Anthropometric, conventional, and biochemical risk factors were evaluated. Thirty-three single nucleotide polymorphisms were genotyped by TaqMan real-time PCR. Bivariate and multivariate logistic regression analysis estimated variables associated with the CAC score. Results After bivariate analysis, PHACTR1 rs1332844 C&amp;gt;T, a downstream regulator of the endothelin-1 gene, showed a significant association with CAC score (p=0.015), together with CDKN2B-AS1 variants rs4977574 A&amp;gt;G in the locus 9p21.3 (p=0.002) and rs1333049 G&amp;gt;C (p=0.010). MTHFD1L gene encodes a mitochondrial enzyme responsible for homocysteine remethylating in methionine, and rs6922269 G&amp;gt;A showed protection against artery calcification (p=0.013). After multivariate logistic regression, PHACTR1 rs1332844 (CT+TT) (p=0.009) and CDKN2B-AS1 rs4977574 A&amp;gt;G (GG) (p=0.002) remained in the equation as independently associated with arterial calcification, together with male sex (p=0.039), age (p&amp;lt;0.0001), hypertension (p=0.001), diabetes (p&amp;lt;0.0001), smoking status (p&amp;lt;0.0001) and obesity (p=0.020). MTHFD1L rs6922269 AA also remained as significant protection from arterial calcification (p=0.027). Conclusion The present work showed two genetic variants, PHACTR1 and CDKN2B-AS1, linked to arterial wall calcification, herewith clinical and environmental risk factors. MTHFD1L showed protection. Understanding the genetic basis of vessel calcification can enable lifestyle changes or pharmacologic therapy to attenuate risk before the disease becomes clinic. More research in this field is critical to understanding the genetic basis of CAD through an intermediate phenotype, coronary arterial wall calcification.

Breast arterial calcification: a potential novel imaging marker for HFpEF

Abstract Background Breast arterial calcification (BAC) on mammography has been shown to associate with cardiovascular disease, however the association with heart failure (HF) remains largely uncharacterised. BAC is a medial arterial calcification process, which is a marker of vascular stiffness, a key contributor to diastolic dysfunction (DD) and HFpEF. We sought to evaluate the association between BAC and HFpEF. Purpose This study aims to assess the relationship between BAC status and HFpEF. Methods This retrospective cross-sectional study included 100 consecutive patients with clinically indicated mammography and echocardiography within 6 months of each other. BAC was visually assessed to determine presence or absence. HFpEF was diagnosed based on combined clinical and echocardiographic assessment. DD was defined by Mitter et. al’s(1) criteria after review of echocardiograms. Logistic regression analysis with Odds Ratio (OR) and (95% confidence intervals) are reported for association with any HF, HFpEF, or DD adjusting for modifiable (body mass index, hypertension, hyperlipidaemia, current smoking, diabetes mellitus) and non-modifiable (age, past smoking breast cancer, past ischaemic heart disease (IHD), atrial fibrillation (AF), chronic kidney disease (CKD)) risk factors. Results The prevalence of BAC was 27% and 13% had HFpEF and 55.8% had DD. Patients with BAC were older (mean age 73±13 vs 57±13, p&amp;lt;0.01) with greater proportion of hypertension (66.67% vs 39.73%, p=0.02), hypercholesterolaemia (70.37% vs 43.84%, p=0.02), AF (p&amp;lt;0.01), previous IHD (p=0.01), and CKD (p&amp;lt;0.01). After adjustment for these variables, BAC was independently associated with HFpEF diagnosis for modifiable risk factors: (OR 2.47 [0.50-12.10], p&amp;lt;0.27) and non-modifiable factors (OR 6.96 [1.72-33.31], p&amp;lt;0.01). BAC was also independently associated with echo defined DD: adjusted for modifiable risk factors (OR 8.67 [2.49-42.16], p&amp;lt;0.01), and non-modifiable risk factors (OR 8.25 [2.44-38.27], p&amp;lt;0.01). Conclusions BAC is associated with HF presence, particularly HFpEF and DD. Further research is required to elucidate the role of shared pathophysiological mechanisms, such as vascular stiffness and general arterial calcification, common to BAC, DD, and HFpEF. In the future, BAC may act as a useful surrogate and opportunistic marker to instigate further review if implemented in established widespread breast-screening programs for detection of subclinical disease.Figure 1:Case example of imaging assess

High prevalence of coronary artery calcium and aortic calcification in adults with repaired coarctation of the aorta and interrupted aortic arch

Abstract Background There is a high rate of late cardiovascular mortality in patients with repaired coarctation of the aorta (CoA) and interrupted aortic arch (IAA). Coronary artery calcium (CAC) is a marker of cardiovascular disease and there is growing evidence for aortic calcification as a predictor. Recent research in the general population suggests any CAC in males &amp;lt;35 years old and females ≤45 years places them at ≥90th percentile. Aims We aimed (1) to determine the prevalence of CAC, thoracic aorta calcification (TAC), and abdominal aorta calcification (AAC) in patients with CoA or IAA repair, and (2) to compare patients to a control group of Tetralogy of Fallot (TOF) patients, a condition with no known increased risk of atherosclerotic cardiovascular disease. Methods Retrospective cohort study of adult survivors of CoA/IAA repair followed up at an adult congenital heart disease (ACHD) clinic. Patients with at least 1 chest, abdomen, or pelvis computerised tomography (CT) scan for any indication were included. The presence/absence of calcification in the coronary arteries or aorta was assessed qualitatively. Patients on antihypertensive and statin therapy were considered hypertensive and hypercholesterolaemic, respectively. Patients were compared to adult survivors of TOF repair with CT scans for any indication (controls). Results Ninety-three CoA/IAA patients (87% CoA/13% IAA, median age at latest follow-up 34 years) had a total of 169 chest and 37 abdomen/pelvis CTs; 82, 93, and 37 patients had at least 1 CT suitable for CAC, TAC, and AAC review, respectively. CAC was present in 22% (18/82), TAC in 33% (31/93), and AAC in 23% (5/22) of CoA/IAA patients. CAC was present in 12% (18/153) and TAC in 11% (18/158) of TOF patients. CoA/IAA patients were more likely to have CAC and TAC than TOF patients (p=0.04 and p&amp;lt;0.0001; respectively) and be younger at the time of diagnosis (CAC p=0.03, TAC p=0.0001) despite TOF patients being older at time of latest CT scan (p=0.0003) (Table 1). Males aged &amp;lt;35 years and females ≤45 years represented 44% (8/18) of CoA/IAA patients with CAC. CoA/IAA patients with CAC were more likely to be hypertensive and hypercholesterolaemic than those without (78% [14/18] vs 48% [31/64], p=0.03; and 28% [5/18] vs 0% [0/64], p&amp;lt;0.0001; respectively) and was similar for TAC (hypertension p=0.005, hypercholesterolaemia p=0.04) but not AAC. After a mean follow-up of 11±7 years from first ACHD clinic, of the 93 patients, 2 patients died, 5 had coronary artery disease (at least mild stenosis on invasive angiography), 3 had a stroke, and 70% (65/93) were considered hypertensive at latest follow-up. Conclusions There is a high prevalence of CAC, aortic calcification, and hypertension in young adults with repaired CoA/IAA. Coronary and thoracic aortic calcification occurs at a younger age compared to controls. Further studies are warranted to assess the impact of aggressive cardiovascular risk reduction in this high-risk group.

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR &amp;lt;60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

The novel role of complement 3 in Wnt5a-mediated vascular smooth muscle cell calcification

Abstract Background Although vascular calcification (VC) is a risk factor for cardiovascular and all-cause mortality, a therapy is not yet available. VC involves the transdifferentiation of vascular smooth muscle cells (VSMC) towards an osteochondrogenic lineage that results in calcium phosphate salts deposition in the arterial wall. We have previously shown an association between plasma WNT5A levels and new onset and progression of coronary artery calcification. Purpose We aimed to study the poorly understood role of Wnt5a in VSMC calcification. Methods Study 1 included 18 patients with coronary artery disease (CAD) undergoing cardiac surgery; VSMC were isolated from their saphenous veins to perform in vitro assays and microarrays. Study 2 included 11 patients with CAD; IMA were treated ex vivo with Wnt5a recombinant protein (rWnt5a) to perform western blot (WB) analyses. Study 3 included 647 patients with CAD; RNA sequencing was performed on samples from their internal mammary arteries (IMA), IMA perivascular adipose (PVAT), and thoracic adipose tissue (ThAT). VSMC and human aortic smooth muscle cells (HASMC) from healthy donors were grown in osteogenic medium in the presence or absence of rWnt5a with or without specific protein inhibitors. Calcium deposition and expression of VC markers (i.e. RUNX2, BMP2, and MSX2) were assessed with a colorimetric assay and by RT-qPCR, respectively. Phosphorylation/activation of non-canonical Wnt pathway effectors was evaluated by WB analyses. Results rWnt5a treatment significantly increased calcium deposition in both VSMC and HASMC at a concentration that activates both JNK and CaMKII, that are effectors of the non-canonical planar cell polarity pathway and the calcium-dependent pathway, respectively. Inhibition of either JNK or CaMKII could not counteract rWnt5a-mediated increase in VSMC calcium deposition; whereas, inhibition of both non-canonical pathway effectors (JNK-i and CaMKII-i) prevented rWnt5a-mediated increase in calcium deposition by VSMC (A) and HASMC. Inhibition of JNK and CaMKII also prevented rWnt5a-induced gene expression of VC markers, such as RUNX2 (B). rWnt5a treatment in IMA increased the activation of JNK and CaMKII. Patients with higher WNT5A levels in IMA had significantly higher RUNX2 levels. By intersecting RNA sequencing and microarray data complement 3 (C3) resulted as the most upregulated gene in rWnt5a-treated VSMC among those genes whose levels positively correlated in IMA with both WNT5A and RUNX2 expression (C). Patients with higher WNT5A levels in IMA, their PVAT, and ThAT had significantly higher C3 levels (D), and patients with higher levels of C3AR1, that is the gene coding for the C3a receptor, had higher VC markers expression. C3 inhibition (C3-i) with a C3AR1 antagonist counteracted Wnt5a-induced VSMC calcium deposition (E). Conclusions Non-canonical Wnt signalling promotes VSMC calcification through C3. Wnt5a may be a therapeutic target in VC.Abstract Figure

Rotational atherectomy versus orbital atherectomy for the treatment of calcified coronary lesions: a systematic review and meta-analysis of 81,873 patients

Abstract Background Previous studies have suggested that pre-treatment of coronary artery calcification with rotational atherectomy (RA) prior to stent deployment can enhance procedural success, but this does not necessarily translate into improved clinical outcomes. Recently, the Orbital Atherectomy (OA) system has been introduced into clinical practice to enhance lesion preparation. Purpose Our study aims to evaluate the safety and efficacy of both RA and OA as pre-treatment strategies before stent deployment in patients with coronary artery calcification. Methods We conducted a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies. These were identified through systematic PubMed, Web of Science, Scopus, Embase, and Cochrane searches until January 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using Stata version 17. Results Our analysis included eleven studies encompassing 81,873 patients. No significant difference was observed between RA and OA in terms of major adverse cardiovascular events (MACE) (RR: 0.81 with 95% CI [0.64, 1.02], P= 0.07). However, OA was significantly associated with a decreased incidence of all-cause mortality (RR: 0.60 with 95% CI [0.52, 0.70], P&amp;lt; 0.01), target vessel revascularization (TVR) (RR: 0.43 with 95% CI [0.22, 0.82], P= 0.01), coronary artery bypass grafting (CABG) (RR: 0.78 with 95% CI [0.62, 0.97], P= 0.03), and fluoroscopy time (MD: -3.93 with 95% CI [-7.39, -0.48], P= 0.03). There was no significant difference between RA and OA in cardiac death (RR: 2.65 with 95% CI [0.94, 7.51], P= 0.07), target lesion revascularization (TLR) (RR: 0.57 with 95% CI [0.23, 1.41], P= 0.22), myocardial infarction (RR: 0.79 with 95% CI [0.62, 1.01], P= 0.06), stent thrombosis (RR: 0.33 with 95% CI [0.09, 1.23], P= 0.10), stroke (RR: 0.76 with 95% CI [0.57, 1.01], P= 0.06), re-admission (RR: 0.76 with 95% CI [0.48, 1.19], P= 0.23), vessel closure (RR: 0.78 with 95% CI [0.18, 3.33], P= 0.74), procedural duration (MD: -5.43 with 95% CI [-21.71, 10.84], P= 0.51), length of hospital stay (MD: 0.21 with 95% CI [-0.47, 0.90], P= 0.54), and contrast amount (MD: -3.68 with 95% CI [-9.37, 2.01], P= 0.21). Conclusion Both RA and OA as pre-treatment strategies before stent deployment demonstrate similar outcomes for numerous cardiovascular events. However, OA is associated with lower rates of all-cause mortality, TVR, CABG, and fluoroscopy time.

Novel deep learning algorithm demonstrates strong performance for detection and quantification of breast arterial calcification and associates with cardiovascular disease

Abstract Background Breast arterial calcification (BAC) on mammography is associated with cardiovascular disease (CVD).1, 2 Given mammography is widely used as part of national breast cancer screening programs, routine reporting of BAC could address current limitations of CVD detection in women. Fully automated artificial intelligence (AI) software can facilitate seamless integration of BAC assessment alongside standard radiological evaluation of mammograms. and advancement in AI imaging software may result in clinically significant, superior BAC detection. Purpose To evaluate the performance of a deep-learning, fully-automated BAC detection algorithm against gold standard human BAC detection, and to evaluate its association with cardiovascular risk and disease. Methods A cohort of 285 women (mean age 61) with 2D digital mammography and CVD assessment with either an anatomic or functional test were evaluated. Cardiovascular risk factors were obtained from medical records. Visual BAC (vBAC) was assessed as present/absent by independent reviewers and BAC was scaled by an algorithm incorporating size, length, density and location (aBAC, 0-100). Diagnostic performance of vBAC and aBAC were compared and expressed as area under the receiver operator characteristic curve (AUC). Cardiovascular risk factor and disease prevalence was compared between vBAC and aBAC with CVD status defined by either abnormal anatomical or functional testing. Results The prevalence of vBAC and aBAC were 30.5% and 59.6%, respectively. The algorithm showed excellent discrimination for BAC detection compared with vBAC (AUC 0.92 [95% CI 0.89-0.98]), with sensitivity 94% and negative predictive value 96%. Interpretation took on average 144 seconds/patient with vBAC and 10 seconds/patient with aBAC (p&amp;lt;0.001). We identified 88 discordant cases (vBAC negative, aBAC positive), which were all represented by ‘faint’ BAC scores (&amp;lt;25). aBAC detected a greater proportion of patients with traditional cardiac risk factors, particularly in women &amp;lt;65 years (Figure 1). CVD was present in 136 (48%), among whom 37.5% were detected by vBAC and 61.7% by aBAC. CVD was present in 42% of the 88 discordant cases. Increasing BAC score was associated with increased relative risk of CVD presence (Figure 2). Conclusion Algorithmic scoring of BAC demonstrates a high performance and is faster to perform when compared to vBAC. Furthermore, it identifies greater proportion of women with higher cardiovascular risk and those with prevalent CVD. Lastly, aBAC detects ‘faint’ (visually missed) lesions that may have significant clinical implications.

Combined mammographic breast density and breast arterial calcification is incrementally predictive of coronary artery disease beyond traditional risk factors

Abstract Background Coronary artery disease (CAD) risk is underestimated in women using current risk stratification tools. The mammographic finding of breast arterial calcification (BAC) associates with CAD. Furthermore, breast adipose tissue, measured through breast density (BD) on mammography (low breast density indicates high adiposity) has shown potential to act as a pro-inflammatory, pro-atherogenic fat deposit. Given its uptake in screening programs, mammography may therefore represent a novel risk stratification tool for cardiovascular disease in women. Purpose To evaluate the association between the combined mammographic features of BD and BAC, with CAD. Methods Single-centre, retrospective, cross-sectional study, including 153 women, mean age 62±10, who had both clinically indicated mammography, and coronary computed tomography angiogram (CCTA) for suspected CAD. CAD risk was identified by the CAD Consortium Score, with a 15% threshold for low and high risk. BD was visually assessed and categorised by 4-level BI-RADS grade with grade A-B representing low density, and C-D representing high density (Figure 1). BAC was visually assessed and categorised as present/absent (Figure 1). CAD was categorised as presence/absence of coronary artery plaque on CCTA. Logistic regression was performed with results presented as Odds Ratio (OR) and [95% Confidence Intervals]. Receiver operator characteristic area under the curve (AUC) was used for model discrimination. Results Low BD (n=103 (67%)) was associated with CAD (OR 3.20 [1.58-6.53], p=0.001, as was BAC presence (n=37 (24%), OR 4.36 [1.58-12], p=0.004). There were 51 (33%) with elevated CAD risk. Participants were categorised into 4 subgroups based on low/high BD and presence/absence of BAC: 29 (19%) had low BD and BAC, 74 (48%) had low BD and no BAC, 8 (5%) had high BD and BAC and 42 (27%) had high BD and no BAC. Significantly higher proportions of CAD were noted with low BD and BAC alone, as well as combined low BD and BAC (Figure 2). Compared with high BD/BAC negative, the presence of low BD and BAC independently associated with CAD (OR 5.27 [1.19-23.3], p=0.03). Significant incremental benefit was seen after adding BD/BAC status to CAD Consortium Score (AUC 0.65 vs. 0.72, p=0.004). Conclusions Combined, and individual mammographic features of low BD and BAC presence are associated with CAD and improve risk prediction beyond standard coronary risk probabilities. Standardised reporting of these features to inform risk identification may be of further benefit and should be tested in prospective screening studies.

Reduced inflammation assessed by pericoronary adipose tissue is associated with coronary plaque calcification

Abstract Introduction Pericoronary adipose tissue attenuation (PCAT) quantified from coronary computed tomography angiography (CCTA) is increasingly recognized as an inflammation marker in coronary artery disease (CAD). Inflamed PCAT has been linked to non-calcified plaque (NCP) and cardiovascular morbidity and mortality. Nevertheless, gaps remain in understanding how PCAT behaves during plaque stabilization. Purpose We investigated associations between coronary artery inflammation assessed by PCAT and the presence and type of coronary plaques, plaque burden, and coronary calcification. Methods An observational study involving 506 patients with suspected chronic coronary syndrome who underwent CCTA. PCAT was averaged across the proximal 40 mm segments of all three coronary vessels to represent the patient level. Plaque presence and types (calcified, mixed, and soft) were assessed. Total, NCP, and calcified plaque (CP) burdens were measured as normalized atheroma volumes. Coronary calcification was quantified using Agatson coronary artery calcification (CAC) score and categorized based on cut-offs of 0, 100, 400. Results The mean PCAT was -81.1 ±6.3 Hounsfield Unit (HU) without plaque and -79.7 ±6.0 HU with plaque (p= 0.01). PCAT differed between calcified (-81.8 HU), mixed (-79.8 HU), and soft (-77.0 HU) plaques (p&amp;lt;0.0001). Multivariate linear analysis (adjusted for clinical risk factors, cardiovascular medication, and tube voltage) showed PCAT positively associated with total plaque burden (estimate= 1.1 [95% CI: 0.3-1.8], p=0.004) and NCP burden (estimate= 2.4 [95% CI: 1.4-3.4]; p&amp;lt;0.0001), while the association with CP burden was negative, but not statistically significant (estimate= -1.7 [95%CI : -4.1-0.7], p=0.2). Multivariate linear analysis, which accounted for both calcified and non-calcified plaque, reaffirmed the positive association to NCP burden (estimate= 2.7 [95% CI: 1.7-3.7]; p&amp;lt;0.0001) and a significant negative association between CP burden (estimate= - 3.3 [95% CI: -5.8- -1.0]; p=0.007) and PCAT. No significant differences in PCAT levels were found among patients with a CAC score of 0 and those with CAC scores exceeding 400, or across different stages of CAC score categories (p&amp;gt;0.8). Conclusion PCAT increased with plaque presence, rising from calcified to mixed to soft plaques. Increased NCP burden associated with higher PCAT, while higher CP burden seemed to reduce PCAT, though not statistical significant. Interestingly, when NCP was absent, higher levels of CP burden were associated with reduced inflammation. This supports the hypothesis of plaque stabilization, proposing that calcification might stabilize the vessel and indirectly contribute to reducing inflammation.Figure 1 PCAT by plaque typesTable 1 PCAT &amp; plaque burden

How to decide appropriate percutaneous coronary intervention (PCI) technique for managing heavy calcified coronary lesions: serial case-report

Background: Coronary artery calcification (CAC) is still challenging for interventional cardiologists. Their contribution to major adverse cardiac events occurs from the high risk of stent thrombosis or in-stent restenosis and target lesion revascularization. Optimal preparation, such as coronary plaque modification before stenting, is required to reduce the risk of periprocedural adverse events. This case presentation aimed to describe the appropriate management of heavy calcified coronary lesions. Case Presentation: Two cases of heavy calcified coronary lesions with different baselines as Acute Coronary Syndromes (ACS) and elective PCI were presented. In our ACS patients, the Primary PCI was done by coronary angioplasty without stenting because of the complexity of the heavily calcified lesion. A referral to tertiary health care was made for further PCI procedures using a combination of calcium-ablation and balloon-based techniques. A treatable complication occurred after the orbital atherectomy was performed with good results. The second case was an elective PCI patient with heavy calcified lesions findings from coronary angiography. The balloon-based technique was performed using non-compliant and scoring balloons without complication and showed good results. Conclusion: The challenging points in managing heavy calcified coronary lesions are procedure complexity and the higher stent failure rate. Many modifying coronary calcification algorithms using advanced modalities have been proposed, which could be used to select the appropriate technique as experienced and increase the success rate. Keyword: balloon-based technique, calcium-ablation technique, heavy calcified coronary lesion, orbital atherectomy

Predictors of debulking devices use by coronary artery calcification classification using cardiac CT

Abstract Background Multi-slice computed tomography (CT) is useful for the non-invasive detection and quantification of coronary calcium burden. However, a definitive parameter based on CT imaging for predicting the need for debulking devices, such as rotational atherectomy (RA) and orbital atherectomy (OAS), has yet to be established. Purpose We aimed to develop a calcification risk score using cardiac CT to predict the use of debulking devices during coronary intervention. Methods In this retrospective, multi-center, observational study in Japan, patients who underwent percutaneous coronary intervention (PCI) were screened. Inclusion criteria were (1) cardiac CT within 6 months prior to PCI, (2) moderate or severe coronary calcification detected on CT, and (3) de novo lesions in a native coronary artery. A total of 349 lesions in 343 patients from 13 hospitals, there were 124 lesions that were treated with debulking devices and 225 lesions without debulking devices. Cardiac CT images were analyzed for circumferential degree, longitudinal length, intracoronary distribution of calcification, peak density, mean density, vessel bend and presence of bifurcation lesions. Data from a random two-thirds (the derivation cohort, n=247) were used to develop a new risk prediction model, which was then tested in the remaining one-third (the validation cohort, n=102). Odds ratios and the risk prediction model were developed using a logistic regression model. The predicted risk was translated into a simplified scoring system (Figure 1A). Results RA was used in 111 lesions and OAS in 23 lesions. Factors selected in the model included circumferential degree (≥270°: 3 points), bifurcation (2 points), longitudinal length (≥8mm: 1 point), and mean density (≥600 HU: 1 point) (Figure 1B). This model demonstrated good discrimination (c-statistic=0.772) and calibration (Hosmer–Lemeshow χ²-statistic=0.885; P=0.64) in the validation cohort (Figure 2). Conclusions The new prediction model based on cardiac CT performed well in predicting the need for debulking devices. This could serve as an objective tool to support a clinical decision to use debulking devices even in cases where intravascular imaging is not applicable.Study flow and Cardiac CT calcium scoreDiscrimination and Calibration