Artificial intelligence in preventive cardiology.

Artificial intelligence (AI) is a field of study that strives to replicate aspects of human intelligence into machines. Preventive cardiology, a subspeciality of cardiovascular (CV) medicine, aims to target and mitigate known risk factors for CV disease (CVD). AI's integration into preventive cardiology may introduce novel treatment interventions and AI-centered clinician assistive tools to reduce the risk of CVD. AI's role in nutrition, weight loss, physical activity, sleep hygiene, blood pressure, dyslipidemia, smoking, alcohol, recreational drugs, and mental health has been investigated. AI has immense potential to be used for the screening, detection, and monitoring of the mentioned risk factors. However, the current literature must be supplemented with future clinical trials to evaluate the capabilities of AI interventions for preventive cardiology. This review discusses present examples, potentials, and limitations of AI's role for the primary and secondary prevention of CVD.

Validation of Signal Intensity Gradient from TOF-MRA for Wall Shear Stress by Phase-Contrast MR.

To validate the correlation between the signal intensity gradient (SIG) from time-of-flight magnetic resonance angiography (TOF-MRA) and wall shear stress (WSS) determined by phase contrast magnetic resonance (PC-MR), we conducted both experimental and human studies. In the experimental study, we measured WSS in four tubes of different sizes with variable flow rates using PC-MR and TOF-MRA. The flow rates of water in the experimental study ranged from 0.06 to 12.75 mL/s, resulting in PC-WSS values between 0.1 and 1.6 dyne/cm2. The correlation between PC-WSS and SIG was statistically significant, showing a coefficient of 0.86 (P < 0.001, R2 = 0.75). The line fit provided the conversion equation as Y = 1.6287X - 1.1563 (Y = PC-WSS, X = SIG). For the human study, 28 subjects underwent TOF-MRA and PC-MR examinations of carotid and vertebral arteries. Arterial PC-WSS and SIG were determined in the same segment for each subject. The arterial PC-WSS ranged from 1.9 to 21.0 dyne/cm2. Both carotid and vertebral arteries showed significant correlations between PC-WSS and SIG, with coefficients of 0.85, 0.86, 0.91, and 0.81 in the right and left carotid and vertebral arteries, respectively. Our results show that SIG from TOF-MRA and SIG-WSS derived from the conversion equation provide concurrent in vivo hemodynamic information on arterial shear stress. This study was registered on ClinicalTrials.gov with the identifier NCT04585971 on October 14, 2020.

Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.

Importance: Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Objective: To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia. Design, Setting, and Participants: This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs. Interventions: All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W. Main Outcomes and Measures: Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs). Results: A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment. Conclusions and Relevance: In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT03175367.

Familial Hypercholesterolemia: Challenges for a High-Risk Population: JACC Focus Seminar 1/3.

The availability of statins, ezetimibe, and PCSK9 inhibitors has significantly improved the prognosis of familial hypercholesterolemia (FH). However, a great number of individuals with FH do not achieve guideline-recommended low-density lipoprotein (LDL) cholesterol levels despite maximal lipid-lowering therapy. Novel therapies that lower LDL independent of LDL receptor activity can help mitigate atherosclerotic cardiovascular disease risk in most homozygous FH and many heterozygous FH patients. However, access to novel therapies remains limited for heterozygous FH patients with persistent elevation of LDL cholesterol despite treatment with multiple classes of cholesterol-lowering therapies. Conduction of cardiovascular outcomes clinical trials in patients with FH can be challenging because of difficulty in recruitment and long periods of follow-up. In the future, the use of validated surrogate measures of atherosclerosis may allow for clinical trials with fewer study participants and shorter duration, thereby expediting access to novel treatments for patients with FH.

Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits.

Background: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems. Methods: Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p<0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR (MVMR) controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels. Results: Our results identified seven disease traits reaching Bonferroni-corrected significance in both the discovery (p<1.92 × 10-5) and replication analyses (p<2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24-1.43, p=2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p<0.05), identifying plasma TG levels as a novel potential risk factor for nine non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10-1.29, p=1.17 × 10-5). Conclusions: Taking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies. Funding: RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).

The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

Quality of Care Among Patients with Diabetes and Cerebrovascular Disease. Insights from The Diabetes Collaborative Registry.

BACKGROUND: Although secondary cardiovascular prevention is a focus among patients with type 2 diabetes (T2D) and coronary artery disease (CAD) or peripheral artery disease (PAD), the application of guideline-recommended therapy in T2D patients and isolated cerebrovascular disease (CeVD) remains unknown. METHODS: In a US outpatient registry, T2D patients with established cardiovascular disease from 2014-2018 were categorized as: isolated CeVD, CeVD plus CAD or PAD, or isolated CAD/PAD. In each group, we determined the proportion with optimal secondary prevention (hemoglobin [Hb]A1C <8%, blood pressure <130/80 mm Hg, use of antithrombotics, use of statins, non-smoking/cessation counseling, and use of glucose-lowering medications with cardioprotective effects (sodium-glucose cotransporter [SGLT]-2 inhibitors, glucagon-like peptide [GLP]-1 receptor agonists, thiazolidinediones [TZDs]). Hierarchical Poisson regression was used to estimate relative rate of achieving each target across groups, adjusted for age and chronic kidney disease (where relevant). RESULTS: Our study included 727,467 T2D outpatients with cardiovascular disease (isolated CeVD [n = 99,777], CeVD plus CAD/PAD [n = 158,361], isolated CAD/PAD [n = 469,329]). Compared with isolated CAD/PAD patients, isolated CeVD patients more often had an HbA1c <8% (adjusted relative risk [aRR] 1.10; 95% confidence interval [CI], 1.08-1.11) but less often had a blood pressure of ≤130/80 mm Hg (aRR 0.93; 95% CI, 0.92-0.94) or were prescribed antithrombotics (0.84; 95% CI, 0.83-0.85), statins (0.86; 95% CI, 0.85-0.87), GLP-1 agonists (0.75; 95% CI, 0.73-0.78), SGLT2 inhibitors (0.73; 95% CI, 0.71-0.76), and TZDs (aRR 0.76; 95% CI, 0.73-0.78). CONCLUSION: Among T2D patients, those with isolated CeVD had the lowest rates of secondary cardiovascular prevention goals attainment. More focus is needed on secondary prevention in patients with CeVD.

Alcohol Consumption and Cardiovascular Health.

BACKGROUND: Studies evaluating alcohol consumption and cardiovascular diseases have shown inconsistent results. METHODS: We performed a systematic review of peer-reviewed publications from an extensive query of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception to March 2022 for all studies that reported the association between alcohol consumption in terms of quantity (daily or weekly amounts) and type of beverage (wine, beer or spirit) and cardiovascular disease events. RESULTS: The study population included a total of 1,579,435 individuals based on 56 cohorts from several countries. We found that moderate wine consumption defined as 1-4 drinks per week was associated with a reduction in risk for cardiovascular mortality when compared with beer or spirits. However, higher risk for cardiovascular disease mortality was typically seen with heavier daily or weekly alcohol consumption across all types of beverages. CONCLUSIONS: It is possible that the observational studies may overestimate the benefits of alcohol for cardiovascular disease outcomes. Although moderate wine consumption is probably associated with low cardiovascular disease events, there are many confounding factors, in particular, lifestyle, genetic, and socioeconomic associations with wine drinking, which likely explain much of the association with wine and reduced cardiovascular disease events. Further prospective study of alcohol and all-cause mortality, including cancer, is needed.

Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Evinacumab for Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).

Failure of cosegregation between a rare STAP1 missense variant and hypercholesterolemia.

Autosomal dominant familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels and an increased risk for atherosclerotic cardiovascular disease. Although rare pathogenic variants in genes encoding the low-density lipoprotein receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 are found in more than 80% of molecularly defined patients with FH, a few rare minor causative genes have been proposed, including the gene encoding signal-transducing adaptor family member 1 (STAP1). Here, we describe a patient with hypercholesterolemia and the rare heterozygous missense variant p.D207N in STAP1. However, extending the pedigree showed failure of the variant to cosegregate with hypercholesterolemia, as both his sons were carriers of the variant and both were also normolipidemic. The findings add to the evidence against STAP1 as a genetic locus for FH.

Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. OBJECTIVES: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. RESULTS: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. CONCLUSIONS: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).

Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial.

BACKGROUND: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). METHODS: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. RESULTS: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25). CONCLUSIONS: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

Dietary Patterns and Incident Heart Failure in U.S. Adults Without Known Coronary Disease.

BACKGROUND: Dietary patterns and associations with incident heart failure (HF) are not well established in the United States. OBJECTIVES: The purpose of this study was to determine associations of 5 dietary patterns with incident HF hospitalizations among U.S. adults. METHODS: The REGARDS (REasons for Geographic and Racial Differences in Stroke) trial is a prospective cohort of black and white adults followed from 2003 to 2007 through 2014. Inclusion criteria included completion of a food frequency questionnaire and no baseline coronary heart disease or HF. Five dietary patterns (convenience, plant-based, sweets, Southern, and alcohol/salads) were derived from principal component analysis. The primary endpoint was incident HF hospitalization. RESULTS: This study included 16,068 participants (mean age 64.0 ± 9.1 years, 58.7% women, 33.6% black participants, 34.0% residents of the stroke belt). After a median of 8.7 years of follow-up, 363 participants had incident HF hospitalizations. Compared with the lowest quartile, the highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of HF in multivariable-adjusted models (hazard ratio: 0.59; 95% confidence interval: 0.41 to 0.86; p = 0.004). Highest adherence to the Southern dietary pattern was associated with a 72% higher risk of HF after adjusting for age, sex, and race and for other potential confounders (education, income, region of residence, total energy intake, smoking, physical activity, and sodium intake; hazard ratio: 1.72; 95% confidence interval: 1.20 to 2.46; p = 0.005). However, the association was attenuated and no longer statistically significant after further adjusting for body mass index in kg/m2, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease. No statistically significant associations were observed with incident HF with reduced or preserved ejection fraction hospitalizations and the dietary patterns. No associations were observed with the other 3 dietary patterns. CONCLUSIONS: Adherence to a plant-based dietary pattern was inversely associated with incident HF risk, whereas the Southern dietary pattern was positively associated with incident HF risk.

Cholesterol-Lowering Agents.

Loss-of-function variants in PCSK9 (proprotein convertase subtilisin-kexin type 9) are associated with lower lifetime risk of atherosclerotic cardiovascular disease) events. Confirmation of these genetic observations in large, prospective clinical trials in participants with atherosclerotic cardiovascular disease has provided guidance on risk stratification and enhanced our knowledge on hitherto unresolved and contentious issues concerning the efficacy and safety of markedly lowering LDL-C (low-density lipoprotein cholesterol). PCSK9 has a broad repertoire of molecular effects. Furthermore, clinical trials with PCSK9 inhibitors demonstrate that reductions in atherosclerotic cardiovascular disease events are more effective in patients with recent myocardial infarction, multiple myocardial infarctions, multivessel coronary artery disease, and lower extremity arterial disease. The potent LDL-C lowering efficacy of PCSK9 inhibitors provides the opportunity for more aggressive LDL-lowering strategies in high-risk patients with atherosclerotic cardiovascular disease and supports the notion that there is no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been associated by a safety profile superior to that of other classes of LDL-lowering agents. These clinical trials provide evidence that LDL lowering with PCSK9 inhibitors is an effective therapy for lowering cardiovascular events in high-risk patients with LDL-C levels ≥70 mg/dL on maximally tolerated oral therapies, including statins and ezetimibe.

Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high-risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999-2002 through 2011-2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins. CKD was defined by an estimated glomerular filtration rate <60 mL/min per 1.73m2 or albumin-to-creatinine ratio ≥30 mg/g. Statin use was identified through a medication inventory. Between 1999-2002 and 2011-2014, the percentage of adults taking statins increased from 17.6% to 35.7% among those with CKD and from 6.8% to 14.7% among those without CKD . After multivariable adjustment, adults with CKD were not more likely to be taking statins compared with those without CKD (prevalence ratio, 1.01; 95% CI] 0.96-1.08). Among adults without a history of cardiovascular disease, those with CKD but not diabetes mellitus were less likely to be taking statins compared with those with diabetes mellitus but not CKD (prevalence ratio, 0.54; 95% CI , 0.44-0.66). Among adults with a history of cardiovascular disease, there was no difference in statin use between those with CKD but not diabetes mellitus versus those with diabetes mellitus but not CKD (prevalence ratio, 0.95; 95% CI , 0.79-1.15). Conclusions CKD does not appear to be a major stimulus for statin use among US adults.

Trends in Utilization of Statin Therapy and Contraindicated Statin Use in HIV--Infected Adults Treated With Antiretroviral Therapy From 2007 Through 2015.

Background HIV is associated with an increased risk for atherosclerotic cardiovascular disease, which may result in many people living with HIV taking a statin. Some statins are contraindicated with certain antiretroviral therapies ( ART ) and other medications commonly used by HIV -infected patients. Methods and Results We analyzed trends in the use of statins, including contraindicated statins, between 2007 and 2015 among HIV -infected patients aged ≥19 years taking ART who had employer-sponsored or Medicare supplemental health insurance in the Marketscan database (n=186 420). Statin use was identified using pharmacy claims. Contraindicated statin use was defined by a pharmacy claim for HIV protease inhibitors, cobicistat, hepatitis C protease inhibitors, anti-infectives, calcium channel blockers, amiodarone, gemfibrozil, or nefazodone followed by a fill for a contraindicated statin type and dosage within 90 days. The percentage of beneficiaries with HIV taking a statin remained unchanged between 2007 (24.6%) and 2015 (24.7%). Among those taking a statin, the percentage taking a contraindicated statin declined from 16.3% in 2007 to 9.0% in 2014 and then increased to 9.8% in 2015. The proportion of contraindicated statin fills attributable to HIV protease inhibitors declined from 63.9% in 2007 to 51.0% in 2015, while those attributable to cobicistat increased from 0% before 2012 to 20.6% in 2015. Conclusions Changes in ART regimens resulted in a decline in contraindicated statin use from 2007 to 2014, but this favorable trend was attenuated in 2015 because of increased use of cobicistat-containing ART regimens.

Ticagrelor and the Prevention of Microvascular Complications in Diabetes Patients with Lower Extremity Arterial Disease; Rationale and Design of the Hema-Kinesis Trial.

BACKGROUND: Lower extremity arterial disease (LEAD) occurs more common in patients with diabetes than without diabetes. Microvascular complications of diabetes contribute to higher rates of adverse limb events in patients with LEAD. Blood flow in the macrocirculation and microcirculation is reduced with increasing low-shear and high-shear blood viscosity. We hypothesize that the adenosine enhancing properties of ticagrelor will reduce low-shear blood viscosity and improve microcirculatory flow in the dorsum of the feet of patients with type 2 diabetes. Ticagrelor is a P2Y12 receptor antagonist with evidence of cardiovascular event reduction in patients with acute coronary syndromes and those with a previous myocardial infarction. In a large multicenter trial of patients with symptomatic LEAD and a history of limb revascularization, ticagrelor was no more effective than clopidogrel in reducing cardiovascular disease events; however, this trial was not designed to investigate microvascular complications of diabetes. DESIGN: Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry. If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.

Systematic Review of Methods Used for the Microvascular Assessment of Peripheral Arterial Disease.

Lower extremity peripheral arterial disease (LEAD) is increasing in prevalence in low with approximately 202 million people affected with LEAD worldwide. Certain subgroups of individuals (cigarette smokers, diabetics) that are particularly high risk for LEAD and major adverse limb events (MALE). Conventionally, the ankle-brachial index (ABI) is the recommended screening test for LEAD. However, the ABI has several limitations, particularly in patients with diabetes. These limitations include increased measurement variability with severity of LEAD, non-compressible calcified arteries inability to detect arterial disease distal to the ankle precludes assessment of disease in the foot where many ulcers can occur, and underestimation of the extent of microvascular occlusive disease. In this systematic review, we discuss methods used for the assessment of microvascular disease and compare outcomes that encompass microvascular flow with the ABI and toe-brachial index (TBI).