Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice

Objective: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ − (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe − / − background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages. Conclusions: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.

260 Impact of ‘atherosclerotic pabulum’ on in hospital mortality for SARS-CoV-2 infection. Is calcium score alone enough to identify at risk patients?

Although the primary cause of death in COVID-19 infection is respiratory failure, there are evidences that cardiac manifestations may contribute to overall mortality and can even be the primary cause of death. More importantly, it is recognized that COVID-19 is associated with a high incidence of thrombotic complications. Two-hundred-eighty-four patients with proven SARS-CoV-2 infection who had a non-contrast Chest CT at our facility were analysed for coronary calcium score. Clinical and radiological data were retrieved. Patients with coronary calcium had higher inflammatory burden at admission (d-dimer, CRP, Procalcitonin) and higher Troponin at admission and at zenith. While there was no correlation with presence of consolidation and ground glass opacities, patients with coronary calcium had higher incidence of bilateral infiltration and higher in-hospital mortality. Peak troponin was associated with higher mortality, intensive care unit admission and mechanical ventilation in both univariable at multivariate analysis. Calcium score has demonstrated to be a good prognostic indicator for in-hospital mortality in patients with SARS-CoV-2 infection. Patients with higher atherosclerotic burden are at higher risk of fatality and complications. Our findings could have significant clinical implications in selecting at risk patients for allocation of resources especially in those with ‘atherosclerotic pabulum’, where inflammation activated by SARS-CoV-2 may play a role in fatal and non-fatal events.

Evaluation of atherosclerosis in patients with chronic kidney disease by measuring carotid intima media thickness: An observational study from a tertiary care center in India

Background: Chronic kidney disease (CKD) is associated with a substantial cardiovascular mortality and morbidity. Besides other factors, accelerated atherosclerosis plays a significant role in this. Carotid intima media thickness (CIMT) is an index of systemic atherosclerosis. By measuring the CIMT with the help of B mode ultrasound at common carotid artery, the overall atherosclerotic burden in CKD patients can be estimated. Accordingly patients at increased risk of premature mortality can be identified so that timely intervention can be taken. Aims and Objectives: The aim of the study was to measure the CIMT at the level of common carotid artery by B mode ultrasound for estimation of atherosclerotic burden in patients with CKD. Materials and Methods: It is a hospital based observational cross-sectional study involving 70 patients carried out in the department of General Medicine of Medical College and Hospital, Kolkata for a period of 1 year. Patients were selected on the basis of certain inclusion and exclusion criteria. They were evaluated based on clinical history, disease duration, physical examination findings and certain investigation parameters such as complete hemogram, renal function tests, serum potassium, lipid profile, urinalysis, urine for albumin-creatinine ratio, ultrasonography of kidney-ureter-bladder, and CIMT value as measured by B mode ultrasound of carotid artery. The data collected were analyzed with a suitable statistical analysis software package. Range, frequencies, percentage, mean, standard deviation, and P value were calculated. P<0.05 was taken as significant. Results: The study showed a strong correlation between CIMT and BMI (r=0.533, P<0.001). CIMT for serum triglyceride levels (≥150 mg/dl) were significantly (P<0.001) high in patients (mean±SD=1.45±0.559) mg/dl in comparison with serum triglyceride levels (<150 mg/dl) (0.98 ± 0.380 mg/d). Patients with high cholesterol of ≥200 mg/dl have a higher CIMT of 1.56±0.574 with P<0.001. There is statistically significant relation of LDL with respect to mean CIMT as P<0.001 at 1% level of significance. Hence, mean CIMT is more in LDL (≥130) than in LDL (<130). CIMT for HDL levels (<40 mg/dl) were high in CKD (mean=1.53±0.518 mg/dl) patients compared to HDL levels (≥40 mg/dl) (mean=10.88±0.291). It was found that mean CIMT was higher in the later stages of kidney disease (Stage 3B, 4 and Stage 5) as compared to early stages (Stages 1, 2, and 3). We also found that the Mean CIMT (1.214±0.531 was higher in patients with CKD compared to sonographically defined normal value (<0.9 mm). Hence, CKD patients who have traditional risk factors for atherosclerosis such as higher BMI, higher serum total cholesterol level, higher serum triglyceride level, higher serum LDL level, and lower serum HDL level have a higher value of CIMT. Conclusion: B-mode ultrasound is a non-invasive sensitive tool for assessment of CIMT. Since CKD is associated with accelerated atherosclerosis and subsequent increased cardiovascular mortality, this modality may help us to identify patients with atherosclerotic burden so that timely intervention can be taken to reduce future cardiovascular complications in CKD patients.

Cardiovascular Risk Factors and Carotid Intima Media Thickness: Mediation and Interaction by Grip Strength

Frailty is often described as being an increased vulnerability to the effects of stressors. There is little research investing how frailty may act as either a mediator or participate in interactions in the associations between risk factors and chronic disease. We will present novel analyses of the Canadian Longitudinal Study on Aging, focusing on the 30,000 study participants who underwent serial physical evaluations at one of 11 data collection sites between 2011 and 2018. Using the 4- way decomposition method elaborated by Vanderweele, we investigate the role of grip strength, as a component of physical frailty, in the effect of cardiovascular risk factors on the atherosclerotic burden of individuals (measured using carotid intima media thickness). Our findings clarify the mechanisms underlying of grip strength in the associations between cardiovascular risk factors and carotid intima media thickness.

Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.

Diameter Reduction Determined Through Carotid Ultrasound Associated With Cardiovascular and All‐Cause Mortality: A Single‐Center Experience of 38 201 Consecutive Patients in Taiwan

Background Few studies have evaluated the prognostic significance of diameter‐based carotid sonographic measurements for mortality. We investigated whether a reduction in diameter of different carotid anatomical segments is associated with cardiovascular and all‐cause mortality in a hospital‐based cohort with universal health care. Methods and Results We conducted a retrospective cohort study of 38 201 patients who underwent carotid duplex ultrasound at a medical center in Taiwan. Carotid sonographic parameters were the diameter reduction percentage in carotid bifurcation, the internal carotid artery, the common carotid artery, and the external carotid artery and the overall carotid atherosclerotic burden score, determined by summing the scores from all segments. The vital status was ascertained by linking data to National Death Registry until 2017. During a median follow‐up of 4.2 years, 5644 participants died, with 1719 deaths attributable to cardiovascular diseases. The multivariable‐adjusted hazard ratios (HRs; 95% CIs) for cardiovascular mortality were 1.33 (1.16‒1.53), 1.58 (1.361.84), and 1.89 (1.58, 2.26) for participants with 30% to <40%, 40% to <50%, and ≥50% reduction in carotid bifurcation diameter, respectively, compared with participants with <30% diameter reduction ( P for trend <0.001). The corresponding HRs (95% CIs) for all‐cause mortality were 1.25 (1.16‒1.34), 1.42 (1.31‒1.54), and 1.60 (1.45‒1.77), respectively. Diameter reduction at other carotid sites and the carotid atherosclerotic burden score exhibited the same dose–response relationship. Conclusions This study suggests that reduction in carotid artery diameter, which can be determined through routinely available sonography, is an independent risk factor for all‐cause and cardiovascular mortality.

Cardiovascular morbidities in postoperative colorectal cancer patients

This retrospective observational study investigated the long-term prevalence of new-onset cardiovascular disease (CVD) and the predictive role of atherosclerotic plaque in the aorta and iliac arteries for CVD in postoperative colorectal cancer (CRC) patients who received surgical treatment between 2014 and 2015. CVD included coronary or cerebrovascular diseases which required treatment and new-onset CVD included peri-and postoperatively diagnosed CVDs or aggravated CVDs that required additional treatment during follow-up. Of the 2,875 patients included in this study, the prevalence of CVD was 8.9% (255/2875) and 141 (4.9%) developed new-onset CVD. Maximum arterial stenosis in the aorta or iliac arteries occurred in 40.8 ± 18.6% of patients with new-onset CVD and 11.6 ± 13.8% of patients without new-onset CVD (p < 0.001). The mean new-onset CVD-free survival time in patients with > 30% and < 30% stenoses were 52.5 [95% confidence intervals (CIs) 50.0–54.9] and 66.5 (95% CIs 66.2–66.8) months, respectively (p < 0.001). The area under the receiver operating characteristic curve of the maximal arterial stenosis for new-onset CVD was 0.911. These results suggest that CRC patients are at risk for developing new-onset CVD, which is associated with reduced survival. Atherosclerotic burden in the aorta or both iliac arteries may help predict future CVD events.

Radial BMD and serum CTX-I can predict the progression of carotid plaque in rheumatoid arthritis: a 3-year prospective cohort study

Objective Patients with rheumatoid arthritis (RA) are almost twice as likely to develop cardiovascular disease (CVD) as those without. However, traditional CVD risks have been shown to underperform in RA patients; thus, we aimed to identify new surrogate risk factors to better reflect their atherosclerotic burden. Methods A total of 380 RA patients with carotid atherosclerosis data were analyzed in this prospective cohort study. The primary outcome was carotid plaque progression over the 3-year follow-up period. Risk parameters assessed for the progression of carotid plaque were categorized as demographics, traditional CVD risks, RA-related risks, and bone parameters. Results The progression of carotid plaque was associated with the level of rheumatoid factor (p = 0.025), serum C-terminal telopeptide of type-I collagen (CTX-I) (p = 0.014), and femur and distal radius bone mass density (BMD) (p = 0.007 and 0.004, respectively), as well as traditional CVD risk factors. In multivariable analyses, the bone parameters of serum CTX-I and distal radius BMD proved to be independent predictors of the progression of carotid plaque along with hyperlipidemia, smoking, and baseline carotid plaque (all, p < 0.05). Adding both serum CTX-I and distal radius BMD increased the carotid plaque progression prediction model’s percentage of explained variance from 24 to 30%. Conclusion High serum CTX-I and lower radius BMD, reflecting high bone turnover, were independent risk factors for the progression of carotid plaque in RA patients, implicating the direct or indirect role of bone metabolism on the atherosclerotic burden.

Inflammatory risk factors are not associated with coronary artery calcification in patients with myeloproliferative philadelphia-negative neoplasms

Background Myeloproliferative Philadelphia-negative Neoplasms (MPNs) are hematological cancers associated with chronic inflammation and endothelial dysfunction, conditions that may lead to development of premature atherosclerosis. Purpose To investigate whether biomarkers of inflammation and endothelial dysfunction are associated with the degree of atherosclerotic burden, measured by Coronary Artery Calcium Score (CACS), in patients with MPNs. Methods Patients with a validated MPN diagnosis; essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF), were recruited between 2016 and 2018 from one single specialized hematologic center. Patients filled out a standardized questionnaire on medical history, current medication, alcohol and smoking habits and family medical history. They were examined by cardiac computed tomography (CT), Endothelial Peripheral Arterial Tone (EndoPAT), and a range of blood analyses. The atherosclerotic burden was evaluated by CACS. High sensitivity C-reactive protein (hs-CRP) and Neutrophil:Lymphocyt Ratio (NLR) were used as indicators of chronic inflammation. EndoPAT was applied to evaluate endothelial dysfunction, which is linked to development of atherosclerosis. The JAK2V617F-mutation is a common gene mutation in MPN-patients. It affects the gene coding the Janus kinase 2 (JAK2) protein, and can be detected by qPCR of peripheral blood or bone marrow. The JAK2V617F-mutation is a risk factor associated with both chronic inflammation and endothelial dysfunction. Multivariable logistic regression analyses were used to identify associations between potential risk factors and a higher CACS value. Results Among 170 included patients, 161 patients completed cardiac CT (mean age 65.5 (SD 10.5), 52% men). Baseline data is presented in Table 1. JAK2V617F-mutation was found in 137 (85%) patients, 53 patients (35%, n=152) had hs-CRP&gt;2.0 mg/L, 107 (67%, n=160) had NLR&gt;2.15 and 32 (21%, n=154) had an abnormal EndoPAT. Overall, 66 patients (41%) had a CACS&gt;100, with no significant difference between ET (41%), PV (42%) and MF (50%) (p=0.3). In patients with a history of ischemic heart disease (IHD), 92% had CACS&gt;100, compared to 37% in patients without prior IHD (p=0.0003). Five independent factors associated with a CACS&gt;100 were identified; age (OR: 1.3 [95% CI 1.1–1.4]), male sex (OR: 15.2 [95% CI 4.0–57.7]), prior IHD (OR: 15.9 [95% CI 1.2–202.4]), smoking (OR: 3.3 [95% CI 1.1–10.1]), and abnormal EndoPAT (OR: 4.8 [95% CI 1.1–20.0]) (Figure 1). Hs-CRP, NLR and JAK2V617F-mutation status were not significantly associated with CACS &gt;100. Conclusion In this cohort of patients with MPNs, markers of chronic inflammation like hs-CRP and NLR were not associated with higher CACS, nor was the JAK2V617F-mutation. Traditional risk factors of cardiovascular disease seem to be sufficient to identify MPN patients with increased atherosclerotic burden, but measuring endothelial dysfunction provides additional information. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Department of Cardiology, Zealand University Hospital, Region Zealand, Denmark Table 1. Baseline characteristics Figure 1. Odds ratio for CACS &gt;100