Risk Of Atherosclerotic Vascular Disease Research Articles

Role of ADAR2-mediated innate immune responses in vascular inflammation and atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG) Background Adenosine-to-inosine (A-to-I) RNA editing is an epitranscriptional regulator of RNA metabolism, catalyzed by the adenosine deaminases acting on RNA-1/-2 (ADAR1/2). Whether ADAR2 play a role in atherosclerotic processes remains elusive. Aim We examined the role of ADAR2 in vascular endothelial cell (EC) immunomodulatory responses and its biological relevance in murine and human atherosclerosis. Methods The role of ADAR2 in atherosclerosis was determined in a double ADAR2 and ApoE knockout mice fed with Western diet for 20 weeks. Three mouse genetic models (global and inducible vascular endothelial cell (iEC)-restricted ADAR2 and IL6ST knockout) were used to determine the role of ADAR2 in IL-6-related innate immunity. Expression levels of ADAR2 were measured in peripheral blood mononuclear cells derived from 533 individuals at risk for atherosclerotic vascular disease. Structural vascular measurements were used, including intima-media thickness (IMT), carotid wall maximum thickness (maxWT), and the number of atheromatous plaques by carotid and femoral artery ultrasonography as surrogate markers of subclinical arterial disease. Study participants were followed for major adverse cardiovascular events (MACE). Results Genetic ablation of ADAR2 resulted in a reduction of atherosclerotic plaque burden and necrotic core in the aorta and brachiocephalic trunk as well as reduced leukocyte infiltration in atherosclerotic plaques without affecting cholesterol levels in mice. Blood analysis revealed decreased pro-inflammatory cytokine levels including IL-6 after treatment of ADAR2/APOE KO mice compared to littermate control mice. Intravital imaging of IL-6-inflamed vascular endothelium showed that rolling and adhesion of leukocyte subsets to vascular wall were impaired by 2-fold in ADAR2-/- or iEC-ADAR2-/- KO mice. In vivo and ex vivo histological examination revealed that endothelial ADAR2 controls endothelial vascular adhesion molecule expression induced by gp130 signaling. ADAR2-deficient transcriptome revealed a selective upregulation of a conserved group of miRNAs targeting the IL6ST mRNA. Multilayered rescue studies including miR-inhibitors restored IL6ST levels after ADAR2 deficiency. In humans, increased ADAR2 expression was independently associated with the presence of CAD, higher C-reactive protein and mean carotid IMT after adjustment for traditional risk factors. Increased ADAR2 at baseline was prospectively associated with accelerated progression of subclinical atherosclerosis reflected by the increased number of carotid plaques at follow-up (OR=3.74, P<0.05). Finally, high ADAR2 levels were independently associated with higher MACE incidence across a median follow-up period of 54 months. Conclusion Posttranscriptional control of vascular inflammation by ADAR2 is integral for the development and progression of atherosclerosis in mice and humans. Our findings suggest that ADAR2 may serve as a promising therapeutic target for atherosclerosis.Role of ADAR2 in atherosclerosis

Two randomized controlled trials of nudges to encourage referrals to centralized pharmacy services for evidence-based statin initiation in high-risk patients: Rationale and design of the SUPER LIPID program

In patients with or at risk for atherosclerotic vascular disease, statins reduce the incidence of major adverse cardiovascular events, but the majority of US adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians' limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. Centralized pharmacy services can fulfill a strategic role for population health management through outreach, education, and statin prescribing for patients at elevated ASCVD risk, but best practices for optimizing referrals of appropriate patients are unknown. SUPER LIPID (NCT05537064) is a program consisting of two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management, conducted within 11 primary care practices in a large community health system. In both trials, patients were eligible for inclusion if they had an assigned primary care provider (PCP) in a participating practice and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive EHR message that appeared during eligible patients' visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient's chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin; secondary endpoints include the proportion of patients prescribed a statin at guideline-recommended intensity, the proportion of patients filling a statin prescription, and serum low-density lipoprotein level. SUPER LIPID is a pair of pragmatic clinical trials assessing the effectiveness of two strategies to encourage referral of appropriate patients to a centralized pharmacy service for lipid management. The trial results will develop the evidence base for simple, scalable, EHR-based strategies to integrate clinical pharmacists into population health management and increase appropriate statin prescribing. clinicaltrials.gov; NCT05537064.

Heart and blood: clonal hematopoiesis

Cardiovascular diseases are among the leading causes of death worldwide, with well-known modifiable risk factors, such as smoking, overweight, lipid metabolism disorders, lack of physical activity and high blood pressure playing asignificant role. Recent studies have now identified "clonal hematopoiesis" as anovel blood-based risk factor. Clonal hematopoiesis arises from mutations in hematopoietic stem cells, which lead to the expansion of mutated blood cells. Mutated cell clones can be detected in over 40% of individuals over 50years old, with more than 15% of those over 90years old harboring large clones. Surprisingly, mutated cells predispose to the development of leukemia only to a minor extent, leading to the term clonal hematopoiesis of indeterminate potential (CHIP); however, it has been shown that CHIP is associated with an increased risk of cardiovascular diseases. Individuals with CHIP-associated gene mutations have an elevated risk of atherosclerotic vascular diseases, stroke and thrombosis. Patients with heart failure with reduced ejection fraction (HFrEF), whether of ischemic or non-ischemic origin and patients with heart failure with preserved ejection fraction (HFpEF) exhibit an increased number of mutated cells in the blood. The presence of CHIP mutations is linked to apoorer prognosis in patients with existing cardiovascular diseases. Future research should aim at a better understanding of the specific effects of different mutations, clone sizes and combinations to develop personalized therapeutic approaches. Various anti-inflammatory therapeutic drugs are available, which can be tested in controlled studies.

Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes.

Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.

Mitochondrial Ca2+ Uptake Drives Endothelial Injury By Radiation Therapy.

Background:Radiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms.Methods:Endothelial-specific MCU (mitochondrial Ca2+ uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro.Results:In cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca2+ transients and the mitochondrial Ca2+ concentration ([Ca2+]mt) and activated MCU. These outcomes correlated with increases in mitochondrial ROS (mtROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA (mtDNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced mtROS production, mtDNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of mtROS, reduced irradiation-induced Ca2+ entry, and preserved both the integrity of the mtDNA and the production of NO, suggesting a feed-forward loop involving [Ca2+]m and mtROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged mtROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and mtDNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO.Conclusions:Irradiation-induced damage to mtDNA is driven by MCU-dependent Ca2+ influx and the generation of mtROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained mtROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and mtROS might be sufficient to mitigate irradiation-induced vascular disease.

CLINICAL EVENT REDUCTIONS IN HIGH-RISK HYPERTENSION PATIENTS TREATED WITH RENAL DENERVATION: 10-YEAR PROJECTIONS BASED ON 3-YEAR FOLLOW-UP FROM THE GLOBAL SYMPLICITY REGISTRY

Objective: Clinical event rates over 3 years have been published for patients with uncontrolled hypertension treated with radiofrequency renal denervation (RDN) in the Global SYMPLICITY Registry (GSR). We estimated 10-year clinical event reductions following RDN vs. a simulated control group without RDN, for two high-risk subgroups and the full GSR cohort. Design and method: A Markov model was used to compare projected 10-year clinical events [stroke, myocardial infarction (MI), cardiovascular death (CVD), heart failure (HF), all-cause death (ACD), and a composite of major adverse cardiac events (MACE, calculated as sum of stroke, MI, and CVD)] for RDN patients vs. a hypothetical control for the high atherosclerotic vascular disease risk (ASCVD) subgroup (n = 737; 69 ± 8 years), the type-2 diabetes mellitus (T2DM) subgroup (n = 1,007; 64 ± 10 years), and for all GSR patients (n = 2,651; 61 ± 12 years). The simulated control assumed maintenance of baseline office systolic blood pressure (oSBP) over time. The model was calibrated to 3-year stroke and MI events reported in the GSR and used published meta-regression data to calculate risk reduction based on cohort-specific changes in oSBP from baseline. Relative risks (RRs), events avoided, and numbers needed to treat (NNTs) were calculated at 3 and 10 years, along with the ratio of 10- vs. 3-year projected events avoided. Results: 10-year MACE events were 35.8% vs. 48.5% (-12.7%, RR = 0.74) for RDN vs. control for all GSR patients, 37.8% vs. 52.4% (-14.6%, RR = 0.72) for the high ASCVD risk cohort, and 40.5% vs. 54.0% (-13.5%, RR = 0.75) for the T2DM cohort. Across all three cohorts, events avoided were highest for stroke and lowest for MI. 10-year NNTs for MACE were comparable between the three cohorts, estimated between 7 to 8. The ratio of model-projected MACE at 10- vs. 3-years was 5.20, 5.46, and 5.03 for the full GSR, high ASCVD risk, and T2DM cohorts, respectively. Conclusions: Model-based projections based on 3- year events observed in the GSR suggest meaningful event reductions after treatment with radiofrequency RDN at 10 years that might be up to 5-times higher than the projected events avoided at 3 years under the assumption of maintained treatment effect versus baseline.

Benefits and limitations of statin use in primary cardiovascular prevention: recent advances.

The status of low‑density lipoprotein (LDL) cholesterol is strong as an essential cause of atherosclerotic vascular disease (ASCVD) and primary target of lipid lowering. Drugs affecting primarily LDL choles-terol through an increase of LDL receptor expression are the backbone of current therapy, and generic statins are generally safe, effective, and inexpensive drugs serving this purpose. Statins are indicated for practically all patients in secondary prevention, whereas treatment in primary prevention (healthy individuals) is based on a calculated 10‑year risk of ASCVD. At "borderline" (from 5% to <7.5%) and "intermediate" (from 7.5% to <20%) risk various biomarkers (eg, coronary artery calcium) are available for accurate assessment of the individual risk. The calculation of a lifetime risk instead of the 10‑year risk can be especially useful in younger people. More information about the benefits and risks of statins in primary prevention in older people (>70 years of age) will be provided by ongoing randomized and controlled trials (STAREE and PREVENTABLE). In this narrative review, I shall present recent advances in the use of statins in younger and older healthy people, and discuss their benefits and potential risks. I also raise a question whether with the current evidence base, most people in affluent societies would benefit from taking statins.

A big data-driven eHealth approach to prevent, detect, and reduce atherosclerotic cardiovascular disease burden

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Organisation for Scientific Research (NWO) eHealth is a promising tool to support citizens and patients to reduce their risk of future atherosclerotic vascular disease (ASCVD). Currently, many eHealth initiatives are developed, however their use is limited. To improve the adoption of eHealth initiatives, personalization is needed according to preferences and understanding of the individual. Together with stakeholders, we used the design thinking method to create a dream user-scenario for an eHealth solution to improve cardiovascular outcomes. This point-of-view shows the essential concepts of such an eHealth initiative and focuses on scientific solutions and the most important challenges faced during its development. In the user-scenario a federated data infrastructure collects distributed medical and non-medical data from different organizations, while ensuring maximal privacy. This data, that is currently not available, is used in a screening model to identify citizens with an increased risk for ASCVD. Citizens at risk are offered the use of an eCoach, which is connected to a counterfactual prediction model to calculate a residual risk for hypothetical interventions. This risk is visualized in a personalized way to support the shared decision making process of personalized lifestyle and healthcare goals. eHealth modules, integrated in the eCoach, encourages the patient in achieving these goals. Relevant outcomes are monitored and are used to adjust the intensity of the modules and follow-up accordingly. To realize this federated data infrastructure, an ethical and legal framework should be developed to ensue responsible data handling.

The role of ω3-polyunsaturated fatty acids in the prevention of atherogenic cardiovascular diseases starting in childhood

Diseases of the cardiovascular system are one of the main causes of morbidity, disability and mortality. One of the most significant risk factors for their development is atherogenic dyslipidemia. Atherosclerotic vascular damage occurs long before clinical manifestation and often begins to progress as early as childhood. This is why children represent the most important cohort for the prevention of cardiovascular diseases of atherosclerotic genesis. Studies show that taking ₃-polyunsaturated fatty acids reduces the risk of atherosclerotic vascular disease in adults and children. The effect is achieved by multidirectional effects on risk factors such as insulin resistance, obesity, diabetes mellitus, dyslipidaemia, arterial hypertension, inflammation and endothelial dysfunction. In children with primary dyslipidemia (heterozygous familial hypercholesterolemia) taking ₃-polyunsaturated fatty acids leads to normalization of serum triglycerides and a moderate decrease in total cholesterol and low-density lipoprotein cholesterol. The most significant therapeutic and prophylactic effects are observed in patients with secondary dyslipidemias caused by obesity and diabetes mellitus, when, besides the decrease in triglycerides and the increase in HDL cholesterol, ₃-polyunsaturated fatty acids increase the insulin sensitivity of cells and tissue, body weight reduction, increase in muscle mass, stabilization of blood pressure and improvement of liver function are observed. Considering pleiotropic protective effect and good tolerability, ₃-polyunsaturated fatty acids can be widely used for primary and secondary prevention of atherosclerotic cardiovascular diseases in children and adolescents.

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning.

Background and aims: Premature mortality due to atherosclerotic vascular disease is very high in Hungary in comparison with international prevalence rates, though the estimated prevalence of familial hypercholesterolemia (FH) is in line with the data of other European countries. Previous studies have shown that high lipoprotein(a)- Lp(a) levels are associated with an increased risk of atherosclerotic vascular diseases in patients with FH. We aimed to assess the associations of serum Lp(a) levels and such vascular diseases in FH using data mining methods and machine learning techniques in the Northern Great Plain region of Hungary. Methods: Medical records of 590,500 patients were included in our study. Based on the data from previously diagnosed FH patients using the Dutch Lipid Clinic Network scores (≥7 was evaluated as probable or definite FH), we trained machine learning models to identify FH patients. Results: We identified 459 patients with FH and 221 of them had data available on Lp(a). Patients with FH had significantly higher Lp(a) levels compared to non-FH subjects [236 (92.5; 698.5) vs. 167 (80.2; 431.5) mg/L, p < .01]. Also 35.3% of FH patients had Lp(a) levels >500 mg/L. Atherosclerotic complications were significantly more frequent in FH patients compared to patients without FH (46.6 vs. 13.9%). However, contrary to several other previous studies, we could not find significant associations between serum Lp(a) levels and atherosclerotic vascular diseases in the studied Hungarian FH patient group. Conclusion: The extremely high burden of vascular disease is mainly explained by the unhealthy lifestyle of our patients (i.e., high prevalence of smoking, unhealthy diet and physical inactivity resulting in obesity and hypertension). The lack of associations between serum Lp(a) levels and atherosclerotic vascular diseases in Hungarian FH patients may be due to the high prevalence of these risk factors, that mask the deleterious effect of Lp(a).

Dietary Influences on Atherosclerotic Cardiovascular Disease Risk.

Professional organizations recommend various healthy dietary patterns for atherosclerotic vascular disease (ASCVD) prevention. The purpose of this review is to discuss the evidence for the recommended healthy dietary patterns and ASCVD risk reduction, as well as briefly review specific areas of controversy. The Mediterranean, Dietary Approach to Stop Hypertension, and plant-based dietary patterns have been associated with lower ASCVD risk in observational studies. The Mediterranean dietary pattern has been demonstrated to reduce ASCVD event risk in a large, randomized, controlled trial. Observational studies demonstrate dietary patterns with higher quality foods are associated with decreased ASCVD risk and mortality. Healthy dietary patterns emphasize higher intakes of plant-based foods, lean animal protein sources, and non-tropical oils, while limiting intakes of sugar-sweetened products, refined grains, and processed meats. Encouraging individuals to consume healthy dietary patterns with high-quality foods can promote ASCVD prevention and overall health.

Early Microvascular Dysfunction: Is the Vasa Vasorum a "Missing Link" in Insulin Resistance and Atherosclerosis.

The arterial vasa vasorum is a specialized microvasculature that provides critical perfusion required for the health of the arterial wall, and is increasingly recognized to play a central role in atherogenesis. Cardio-metabolic disease (CMD) (including hypertension, metabolic syndrome, obesity, diabetes, and pre-diabetes) is associated with insulin resistance, and characteristically injures the microvasculature in multiple tissues, (e.g., the eye, kidney, muscle, and heart). CMD also increases the risk for atherosclerotic vascular disease. Despite this, the impact of CMD on vasa vasorum structure and function has been little studied. Here we review emerging information on the early impact of CMD on the microvasculature in multiple tissues and consider the potential impact on atherosclerosis development and progression, if vasa vasorum is similarly affected.

Challenges of Cardio-Kidney Composite Outcomes in Large-Scale Clinical Trials.

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function overlap and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes. Primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest in formally acknowledging, defining, and using composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in use of such outcomes that should be considered and addressed before their incorporation into such trials.

Low plantar skin perfusion pressure predicts long-term atherosclerotic vascular events and mortality in maintenance haemodialysis patients

Background and aimsEnd-stage renal disease is associated with an increased risk of atherosclerotic vascular disease (AVD). We investigated whether low plantar skin perfusion pressure (SPP), a useful indicator of peripheral arterial disease (PAD), predicts systemic AVD events and mortality in outpatients undergoing maintenance haemodialysis (HD). MethodsA total of 206 HD patients were enrolled and followed for 5 years. They were divided into 3 groups according to measured SPP: group 1 (G1), SPP >70 mmHg (n = 123); G2, SPP 50–70 mmHg (n = 61); and G3, SPP <50 mmHg (n = 22). ResultsDuring the follow-up period (median, 4.2 years), 56 AVD events (27.2%) and 68 deaths (33.0%) occurred. In G1, G2, and G3, the event-free survival rates were 74%, 55% and 19%, respectively, for AVD events (p < 0.01) and 73%, 54% and 26%, respectively, for mortality (p < 0.01). A Cox multivariate analysis showed that lower SPP was an independent predictor for AVD events [hazard ratio (HR) 3.12, 95% confidence interval (CI) 1.45–6.77, p < 0.01 for G3 vs. G1] and mortality (HR 3.06, 95% CI 1.57–5.98, p < 0.01 for G3 vs. G1). Furthermore, the addition of the SPP value to a model with established risk factors improved the predictability of increasing the net reclassification improvement (NRI; 0.463, p < 0.01) and integrated discrimination improvement (IDI; 0.039, p < 0.01) for AVD events. Similar results were obtained for mortality. ConclusionsLow plantar SPP can stratify risk and improve the predictability of both systemic AVD events and mortality in the maintenance HD population.

Revascularization may accelerate renal dysfunction in hypertensive patients with moderate atherosclerotic stenosis of renal arteries

Atherosclerotic renal artery stenosis (ARAS) accounts for more than 90% of cases with renal artery stenosis, which is the recognized cause of secondary hypertension, renal dysfunction and acute pulmonary edema. It is estimated that about 15% of patients with hypertension also have different degrees of ARAS at the same time. Hypertension is known to be associated with the risk of atherosclerotic vascular disease; these two conditions usually co-exist and interact with each other. At present, many studies have focused on how to intervene ARAS correctly or just optimal medical therapy (OMT). For patients with severe ARAS, stent implantation seems to be able to receive better clinical benefits because it can avoid renal ischemic injury; however, it remains inconclusive whether stent implantation is suitable for the essential hypertension patients accompanied with mild to moderate ARAS. We speculate that renal artery revascularization may accelerate renal dysfunction in essential hypertensive patients accompanied with mild to moderate ARAS, especially when hypertension could not be controlled within the normal range after the revascularization.

ST Elevation Myocardial Infarction as Presenting Feature of C-ANCA Vasculitis: A Case of a Diagnostic Dilemma.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS). Although uncommon, it should be included in the differential diagnosis for middle-aged patients without elevated atherosclerotic vascular disease risk or a family history of cardiovascular disease. SCAD is associated with postpartum women; however, reports noting its association with autoimmune disease and vasculopathy in other populations have recently gained prominence. We report a case of a 41-year-old male who was found to have SCAD after presenting with ST segment elevation myocardial infarction in the context of episodic vision loss, and who later underwent work-up for C-ANCA vasculitis and was successfully treated with corticosteroids.LEARNING POINTSSCAD is most common in middle-aged females. However, it can present in male patients, and it should raise suspicion of underlying vasculopathy.Eosinophilic vasculitis may mimic parasitic infection.C-ANCA vasculitis can be associated with SCAD.

Clinical and Genetic Characteristics of Familial Hypercholesterolemia at Sultan Qaboos University Hospital in Oman.

ObjectivesWe sought to describe the clinical and genetic characteristics of patients with familial hypercholesterolemia (FH) that presented to the lipid clinic at Sultan Qaboos University Hospital, Muscat, Oman.MethodsPatients who presented with high low-density lipoprotein cholesterol (LDL-C) levels (> 189.0 mg/dL or 4.9 mmol/L) were recruited to the study. FH was diagnosed according to the Dutch Lipid Clinic Network criteria. Analyses were performed using univariate statistics.ResultsThe study enrolled 450 patients with a mean age of 48.0±12.0 years, 56.0% (n = 252) were males and 11.3% (n = 51) were smokers. At admission, the proportion of ‘probable/definite’, ‘possible’, and ‘unlikely’ FH were 27.6% (n = 124), 70.0% (n = 315), and 2.4% (n = 11), respectively. Overall, 26.0% (n = 117) of patients had hypertension, 22.4% (n = 101) had a history of coronary artery disease, and 17.3% (n = 78) had diabetes mellitus. Those with ‘probable/definite’ FH were more likely to be prescribed high-intensity statin therapy (75.8% vs. 54.5%; p < 0.001) and statin ezetimibe combination (50.8% vs. 27.3%; p < 0.001) when compared to the ‘unlikely’ FH cohort. Additionally, those with very high atherosclerotic vascular disease (ASCVD) risk were also associated with high-intensity statin therapy (54.7% vs. 42.7%; p = 0.006) and statin ezetimibe combination (26.4% vs. 17.2%; p = 0.023). Patients with ‘probable/definite’ FH were less likely to achieve their LDL-C goal attainment compared to those with ‘unlikely’ FH (13.0% vs. 57.1%; p < 0.001). Furthermore, those with very high ASCVD risk were less likely to achieve their LDL-C goals compared to the high ASCVD risk cohort (9.6% vs. 32.0%; p < 0.001).ConclusionsFH patients are underdiagnosed, undertreated, and less likely to attain their LDL-C goals in Oman.

Abstract 28: Regular Aerobic Exercise Counteracts Endothelial Vasomotor Dysfunction Associated With Insufficient Sleep

Insufficient sleep, defined as chronic short sleep duration (&lt;7 h/night), is an independent risk factor for cardiovascular disease (CVD). We have previously demonstrated that insufficient sleep is associated with reduced endothelium-dependent vasodilation and enhanced endothelin (ET)-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor regulation is thought to contribute mechanistically to the increased risk of atherosclerotic vascular disease incurred with chronic insufficient sleep. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn reducing cardiovascular risk. It is currently unknown if regular aerobic exercise can counteract the negative impact of insufficient sleep on endothelial vasomotor regulation. We tested the hypotheses that regular aerobic exercise would: 1) improve endothelial vasodilation; and 2) decrease ET-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep less than 7 h/night. We studied 36 healthy, middle-aged adults: 16 with normal sleep duration (10M/6F; age: 57±2 yr; sleep duration: 7.4±0.1 h/night) and 20 with short sleep duration (11M/9F; 56±1 yr; sleep duration: 6.2±0.1 h/night). The 20 short sleepers completed a 3-month aerobic exercise training intervention. Forearm blood flow (FBF; plethysmography) was determined in response to intra-arterial doses of acetylcholine (ACh), sodium nitroprusside (SNP), BQ-123 (ET A receptor antagonist) and ACh + BQ-123 in both groups and after the exercise intervention in the short sleepers. As expected, forearm vasodilator responses to ACh were lower (20%; P&lt;0.05) in the short (from 4.2±0.2 to 10.5±0.6 mL/100 mL tissue/min) vs normal (4.2±0.2 to 12.7±0.6 mL/100 mL tissue/min) sleepers. FBF responses to SNP were comparable between the groups. In response to BQ-123, short sleep group had a greater increase in resting FBF than normal sleep group (~25% vs ~8%; P&lt; 0.05). ACh+BQ-123 resulted in an ~25% increase in the ACh-vasodilation in the short sleep group only. After exercise training, although nightly sleep duration was not affected (6.4±0.1 h/night), ACh-mediated vasodilation was ~20% higher (P&lt;0.05), ET-1-mediated vasoconstriction was ~90% lower (P&lt;0.05) and vasodilator response to ACh was not significantly increased with ET A receptor blockade. These results indicate that regular aerobic exercise can reverse the negative influence of insufficient sleep on endothelial vasomotor function, independent of changes in nightly sleep duration.

Relationship between lower limb vascular characteristics, peripheral arterial disease and gait in rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with higher risk of atherosclerotic vascular disease, including peripheral arterial disease (PAD). The aim of this study was to measure lower limb vascular characteristics (indicative of PAD), using non-invasive chairside testing methods, in people with RA compared to matched controls, and to determine the association between vascular characteristics and gait velocity as a measure of functional capacity in people with RA. This was a cross-sectional pilot study which measured lower limb vascular characteristics (bilateral continuous wave Doppler, toe brachial index [TBI] and ankle brachial index [ABI]) and gait velocity (6-m walk test) in people with RA and controls. Differences in vascular characteristics between groups were determined using linear regression models, and associations between vascular characteristics and gait were determined using logistic regression models. Seventy-two participants were included: 34 participants with RA mean disease duration 26.2 (SD 12.1) and 38 age- and sex-matched controls. The control group contained 30 females (79%), and the RA group had 28 females (82%). There were no significant differences between the RA and control groups for lower limb vascular characteristics. People with RA walked significantly slower compared to controls (1.10m/s vs 0.91m/s, P<.001). People with RA who had abnormal TBI, or abnormal qualitative Doppler walked significantly slower compared to those with normal TBI (0.86m/s vs 0.95m/s, P=.043 and 0.81m/s, vs 0.93m/s, P=.028). There was no significant association between ABI and gait velocity. This study did not identify different lower limb vascular characteristics in people with RA compared to matched controls. However, in people with RA, abnormal Doppler and TBI results are associated with slower walking velocity.

Vegetable diversity in relation with subclinical atherosclerosis and 15-year atherosclerotic vascular disease deaths in older adult women.

Increasing vegetable intake and diversity are recommended to maintain better health. Evidence for the health benefits of vegetable diversity, separate from total intake, is scarce. We aimed to investigate the associations of vegetable diversity with subclinical measures of atherosclerosis and atherosclerotic vascular disease (ASVD) mortality. Vegetable diversity was assessed within a validated food frequency questionnaire using a single question, 'How many different vegetables do you usually consume each day (< 1 to ≥ 6 per day)'. Cox proportional hazards modelling was used to examine the association between vegetable diversity and ASVD mortality in 1226 women aged ≥ 70years without clinical ASVD or diabetes mellitus at baseline (1998). In 2001, B-mode ultrasonography was used to measure common carotid artery intima-media thickness (CCA-IMT) (n = 954) and carotid plaque severity (n = 968). Over 15years (15,947 person-years) of follow-up, 238 ASVD-related deaths were recorded. For each additional different vegetable consumed per day, there was 17% lower hazard for ASVD mortality (HR = 0.83, 95% CI 0.78, 0.93, P = 0.001); a 1.7% lower mean CCA-IMT (B ± SE: - 0.013 ± 0.004, P < 0.001); and a 1.8% lower maximum CCA-IMT (B ± SE: - 0.017 ± 0.004, P < 0.001). Further adjustment for total vegetable intake attenuated the association between vegetable diversity and ASVD mortality (P = 0.114), but not CCA-IMT (P = 0.024). No association was observed between vegetable diversity and carotid plaque severity (P > 0.05). Vegetable diversity may contribute to benefits in lowering risk of ASVD in older women. The reduction in risk is partly explained by increased total vegetable consumption. The Perth Longitudinal Study of Aging in Women (PLSAW) trial registration ID is ACTRN12617000640303. This study was retrospectively registered on the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au.