Colchicine for the Prevention of Cardiovascular Disease: Potential Global Implementation.

PURPOSE OF REVIEW: Targeting traditional cardiovascular risk factors is effective in reducing recurrent cardiovascular events, yet the presence of residual cardiovascular risk due to underlying systemic inflammation is a largely unaddressed opportunity. This review aims to comprehensively assess the evolving role of colchicine as a therapeutic approach targeting residual inflammatory risk in the context of those with coronary artery disease (CAD). RECENT FINDINGS: Inflammation plays a significant role in promoting atherosclerosis, and targeting anti-inflammatory pathways has the potential to decrease cardiovascular events. Low-dose colchicine (0.5 mg/day orally), when added to guideline-directed medical care for CAD, safely decreases major adverse cardiovascular events (MACE) by 31% in stable atherosclerosis patients and 23% in those after recent myocardial infarctions. Meta-analyses of recent randomized control trials further support both the efficacy and safety of colchicine, particularly when added to other standard cardiovascular therapies, including statin therapy. The European Society of Cardiology and other national guidelines endorse the use of low-dose colchicine in patients across the spectrum of CAD. Recently, colchicine was FDA-approved in the United States as the first anti-inflammatory therapy for the reduction of cardiovascular events. In a period of a rising incidence of CAD across the globe, colchicine represents a unique opportunity to decrease MACE due to its large magnitude of benefits and general affordability. However, challenges with drug interactions must be addressed, especially in those regions where HIV, hepatitis, and tuberculosis are prevalent. Colchicine is safe and effective at reducing cardiovascular events across a broad spectrum of coronary syndromes. The ability to simultaneously target traditional risk factors and mitigate residual inflammatory risk marks a substantial advancement in cardiovascular prevention strategies, heralding a new era in the global battle against CAD.

Burden of cardiometabolic risk factors and vascular health.

BACKGROUND: Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk. METHODS: Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity. RESULTS: A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors. CONCLUSIONS: We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.

Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases: A Systematic Review and Meta-Analysis.

Importance: Janus kinase (JAK) inhibitors are an effective treatment option for patients with certain skin-related conditions, such as atopic dermatitis, alopecia areata, and vitiligo, but there is a current US Food and Drug Administration (FDA) boxed warning label for oral and topical JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infections, malignant neoplasm, and death. However, this boxed warning was precipitated by results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, which only included patients with rheumatoid arthritis, and the same association may not be observed in dermatologic conditions. Objective: To determine the risk of all-cause mortality, MACE, and VTE with JAK inhibitors in patients with dermatologic conditions. Data Sources: PubMed and ClinicalTrials.gov were searched from database inception to April 1, 2023. Study Selection: This review included phase 3 randomized clinical trials with a placebo/active comparator group of JAK inhibitors used for a dermatologic indication with FDA approval or pending approval or with European Union or Japanese approval. Studies without a comparison group, case reports, observational studies, and review articles were excluded. Data Extraction and Synthesis: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Adverse events using odds ratios (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method. Studies were screened, data abstracted, and quality assessed by 2 independent authors. The protocol was prospectively registered with PROSPERO. Main Outcomes and Measures: Primary outcomes were a composite of adjudicated MACE and all-cause mortality, and VTE. Results: The analysis included 35 randomized clinical trials with 20 651 patients (mean [SD] age, 38.5 [10.1] years; male, 54%) and a mean (SD) follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR, 0.83; 95% CI, 0.44-1.57) or VTE (OR, 0.52; 95% CI, 0.26-1.04). Conclusions and Relevance: In this systematic review and meta-analysis, use of JAK inhibitors was not associated with increased risk of all-cause mortality, MACE, and VTE compared to the placebo/active comparator groups. Additional trials with long-term follow-up are needed to better understand the safety risks of JAK inhibitors used for dermatologic indications.

Evaluation and management of pericarditis in rheumatic diseases.

ABSTRACT: This review summarizes the evaluation for underlying rheumatic conditions in patients presenting with acute pericarditis, treatment considerations for specific rheumatic conditions, and the role of imaging in diagnosis and monitoring. Pericarditis may be one of the initial presentations of a rheumatic disease or identified in a patient with known rheumatic disease. There is also growing evidence for using anti-inflammatory and immunosuppressive agents for treating recurrent pericarditis, which can overlap with the treatment of rheumatic diseases.

Cardiovascular Risk Management in Patients Treated with JAK Inhibitors.

ABSTRACT: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in the pathogenesis of many immune-mediated inflammatory diseases (IMIDs). Although Janus kinase inhibitors (JAKi) are an effective treatment for several IMIDs, they have come under scrutiny as a class due to a potential risk of venous thromboembolism (VTE) and cardiovascular (CV) events, specifically noted with the oral JAKi, tofacitinib, as reported in the ORAL Surveillance Trial of a high CV risk rheumatoid arthritis population. This trial resulted in a black box warning from the Food and Drug Administration and European Medicines Agency regarding risk of VTE and CV events that was extended across several types of JAKi (including topical ruxolitinib) when treating IMIDs, leading to considerable controversy. Included is an up-to-date review of the current and rapidly evolving literature on CV risk in patients with IMIDs on JAKi therapy, including identification of potential risk factors for future VTE and CV events on JAKi therapy. We suggest a comprehensive, multimodal, and systematic approach for evaluation of CV risk in patients considering taking JAKi and emphasize that cardiologists play an important role in risk stratification and mitigation for patients with high CV risk factors or on long-term JAKi therapies.

An inflammatory transcriptomic signature in psoriasis associates with future cardiovascular events.

BACKGROUND: Psoriasis is an inflammatory skin disease associated with increased cardiovascular (CV) risk, whose pathogenesis is not fully known. OBJECTIVE: We identified a transcriptomic signature in psoriasis and investigated its association with prevalent and future risk of a CV event to understand the connection between psoriasis and CV disease (CVD). METHODS: Psoriasis patients (n = 37) with a history of moderate-severe skin disease without CVD and 11 matched controls underwent whole blood RNA sequencing. This transcriptomic signature in psoriasis versus controls was evaluated in two CVD cohorts: Women referred for cardiac catheterization with (n = 76) versus without (n = 97) myocardial infarction (MI), and patients with peripheral artery disease (n = 106) followed over 2.5 years for major adverse CV or limb events (MACLE). The association between genes differentially expressed in psoriasis and prevalent and incident CV events was assed. RESULTS: In psoriasis, median age was 44 (IQR; 34-51) years, 49% male and ACC/AHA ASCVD Risk Score of 1.0% (0.6-3.4) with no significant difference versus controls. The median psoriasis area and severity index score (PASI) was 4.0 (IQR 2.9-8.2) with 36% on biologic therapy. Overall, 247 whole blood genes were upregulated and 228 downregulated in psoriasis versus controls (p < 0.05), and 1302 genes positively and 1244 genes negatively correlated with PASI (p < 0.05). Seventy-three genes overlapped between psoriasis prevalence and PASI with key regulators identified as IL-6, IL-1ß and interferon gamma. In the CVD cohorts, 50 of 73 genes (68%) identified in psoriasis associated with prevalent MI, and 29 (40%) with incident MACLE. Key regulator transcripts identified in psoriasis and CVD cohorts included SOCS3, BCL3, OSM, PIM2, PIM3 and STAT5A. CONCLUSIONS: A whole blood transcriptomic signature of psoriasis diagnosis and severity associated with prevalent MI and incident MACLE. These data have implications for better understanding the link between psoriasis, systemic inflammation and CVD.

Autoimmune diseases and cardiovascular risk.

There are more than 80 different autoimmune diseases which collectively affect 4-8% of the world's population. In a recent study published in Lancet, Conrad et al. found that 19 autoimmune diseases are associated with a composite of cardiovascular disease (CVD). Inflammation promotes atherosclerotic CVD with psoriasis and rheumatoid arthritis recognized as CVD risk enhancers. New strategies are needed to identify and mitigate the impact of chronic inflammation on CVD-related morbidity and mortality.

Cardiovascular and Venous Thromboembolic Risk With Janus Kinase Inhibitors in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis of Randomized Trials.

OBJECTIVE: Janus kinase (JAK) inhibition effectively treats immune-mediated inflammatory diseases (IMIDs); however, concern over the risk of major adverse cardiac events (MACE) and venous thromboembolism (VTE) remains. We aimed to evaluate the safety (VTE and MACE outcomes) of JAK inhibitors in the treatment of IMIDs. METHODS: A search in PubMed, Embase, and ClinicalTrials.gov databases was conducted for randomized clinical trials (RCTs) of JAK inhibitors across IMIDs. Primary outcomes were VTE and MACE with JAK inhibitors compared with placebo and active comparator arms stratified by follow-up time. RESULTS: Sixty-six RCTs enrolled 38,574 patients with a mean age of 48.8 years and a mean follow-up of 10.5 months. JAK inhibitors had a numerically higher rate of VTE when compared with controls (odds ratio [OR] 1.65; 95% confidence interval [CI]: 0.97-2.79), driven by trials with a follow-up duration of 12 or more months (OR 2.17; 95% CI: 1.16-4.05; Pinteraction = 0.05). When compared with active comparators, JAK inhibitors increased VTE in clinical trials with 12 or more months' versus less than 12 months' follow-up time (OR 2.38 [95% CI: 1.24-4.57] vs 0.30 [95% CI: 0.07-1.26], respectively; Pinteraction = 0.01). No increased risk of VTE was seen when comparing JAK inhibitors with placebo arms. For the outcome of MACE, the results were largely similar but did not reach statistical significance (OR 1.19; 95% CI: 0.86-1.64). CONCLUSION: JAK inhibitors when compared with active comparator arms increased the risk of VTE, which was dependent on duration of exposure. Future clinical trials with extended follow-up are needed to clarify the safety profiles of JAK inhibitors.

Statin therapy upregulates arachidonic acid status via enhanced endogenous synthesis in patients with plaque psoriasis.

Circulating fatty acids (FA) may be important in the psoriatic pro-inflammatory phenotype. FADS1 converts linoleic acid (LA) to arachidonic acid (AA), a precursor to potent signaling molecules. HMG-CoA reductase inhibitors (statins) increase FADS1/2 expression in vitro. Psoriasis patients (42 ± 14 years/age, 47% male) were randomized to 40 mg of atorvastatin (n = 20) or nothing (n = 10) for two weeks and plasma FA measured pre and post treatment. After treatment, LDL-C was 44% lower in the statin compared to the no-treatment group. Statins increased FADS1/2 expression, and lowered LA 12% (33% - > 29%, p<0.001) and raised AA 14% (7.7% - > 9.0%, p<0.01) with no change in the no-treatment group. In psoriasis, statins enhance AA and decrease LA, consistent with the action of enhanced FADS expression in vivo. Therapies intended to blunt the effects of AA on platelet aggregation, such as aspirin or omega-3 fatty acids, may require dose adjustment when co-administered with atorvastatin. NCT: NCT03228017.

Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris.

Psoriasis increases the risk of cardiovascular disease (CVD). Biomarkers for cardiovascular (CV) risk stratification in psoriasis are lacking, and the effects of psoriasis biologics on CV risk reduction remain unclear. The goal of this study was to identify biomarkers of CV risk in psoriasis blood that are reduced by ustekinumab. We quantified 276 inflammatory and CV-related serum proteins with Olink's multiplex assay in 10 psoriasis patients (vs. 18 healthy controls) and after 12 weeks of ustekinumab treatment. For each protein down-regulated after treatment, the literature was reviewed for studies assessing the protein's association with CVD. Data were collected from each study to calculate CV risk thresholds for each protein, which were compared with protein levels in psoriasis patients before and after treatment. Our results showed that 43 out of 276 proteins were down-regulated after treatment, 25 of which were initially up-regulated at baseline (vs. controls, all p-values ≤0.1). 8 down-regulated proteins were initially elevated above thresholds associated with enhanced CV risk in the literature (myeloperoxidase, C-X-C motif chemokine 10, E-selectin, interleukin-6, cystatin B, von Willebrand factor, tumor necrosis factor receptor 1 and N-terminal prohormone brain natriuretic peptide). Treatment lowered these proteins to below their risk thresholds, except for IL-6, which was lowered but remained at its risk threshold despite successful psoriasis skin treatment. In summary, 12 weeks of ustekinumab treatment reduced serum proteins present at levels associated with CV risk in psoriasis patients. Further studies can evaluate these proteins as potential ustekinumab-modulated biomarkers of CV risk in psoriasis and the impact of ustekinumab on CV risk reduction.

Antiplatelet Effects of Clopidogrel Vs Aspirin in Virologically Controlled HIV: A Randomized Controlled Trial.

Patients with HIV exhibit platelet activation and increased risk of cardiovascular disease, the prevention of which is not fully known. Fifty-five HIV-positive patients were randomized to clopidogrel, aspirin, or no-treatment for 14 days, and the platelet phenotype and ability to induce endothelial inflammation assessed. Clopidogrel as opposed to aspirin and no-treatment reduced platelet activation (P-selectin and PAC-1 expression). Compared with baseline, platelet-induced proinflammatory transcript expression of cultured endothelial cells were reduced in those assigned to clopidogrel, with no change in the aspirin and no-treatment arms. In HIV, clinical trials of clopidogrel to prevent cardiovascular disease are warranted. (Antiplatelet Therapy in HIV; NCT02559414).

Solar Activity Is Associated With Diastolic and Systolic Blood Pressure in Elderly Adults.

Background Since solar activity and related geomagnetic disturbances modulate autonomic nervous system activity, we hypothesized that these events would be associated with blood pressure (BP). Methods and Results We studied 675 elderly men from the Normative Aging Study (Boston, MA) with 1949 BP measurements between 2000 and 2017. Mixed-effects regression models were used to investigate the association of average 1-day (ie, day of BP measurement) to 28-day interplanetary magnetic field intensity, sunspot number, and a dichotomized measure of global geomagnetic activity (Kp index) in 4-day increments with diastolic and systolic BP. We adjusted for meteorological conditions and other covariates associated with BP, and in additional models adjusted for ambient air pollutants (particulate matter with an aerodynamic diameter ≤2.5 µm, black carbon, and particle number) and ambient particle radioactivity. There were positive associations between interplanetary magnetic field, sunspot number, and Kp index and BP that were greatest with these exposures averaged over 16 through 28 days before BP measurement. An interquartile range increase of 16-day interplanetary magnetic field and sunspot number and higher Kp index were associated with a 2.5 (95% CI, 1.7‒3.2), 2.8 (95% CI, 2.1‒3.4), and 1.7 (95% CI, 0.8‒2.5) mm Hg increase, respectively, for diastolic BP as well as a 2.1 (95% CI, 0.7‒3.6), 2.7 (95% CI, 1.5‒4.0), and 0.4 (95% CI, -1.2 to 2.1) mm Hg increase, respectively, for systolic BP. Associations remained after adjustment for ambient air pollutants and ambient particle radioactivity. Conclusions Solar activity and solar-driven geomagnetic disturbances were positively associated with BP, suggesting that these natural phenomena influence BP in elderly men.

Psoriasis and Cardiovascular Disease: Novel Mechanisms and Evolving Therapeutics.

PURPOSE OF REVIEW: Psoriasis is a chronic inflammatory skin condition that is associated with increased cardiovascular risk compared to those without psoriasis. This review will cover emerging mechanisms of cardiovascular risk, key pathways targeted with biologic therapies, and the current evidence on therapies to modulate this risk in patients with psoriasis. RECENT FINDINGS: Recent scientific work has highlighted mechanisms that contribute to this enhanced risk, including the role of vascular endothelial dysfunction, platelet activation, dyslipidemia, and increased cardiometabolic comorbidities. Newer biologic and targeted synthetic therapies have transformed psoriasis treatment with high rates of clinical remission and durable skin disease control now possible. Epidemiological evidence suggests that many of these therapies may lower cardiovascular risk in psoriasis, although prospective interventional data is lacking (or mixed). Recently, caution has also been raised that some treatments may negatively affect cardiovascular risk. Overall, the current data suggests a positive or neutral ability to reduce cardiovascular risk for TNF, IL-17A, and IL-12/23p40 inhibitors, but current evidence remains conflicting for anti-IL-23/p19 and JAK inhibitors. More studies that include prospective cohorts, larger number of patients, treatment duration, and validated surrogate outcomes are needed to better evaluate the role of biologic therapies on cardiovascular risk in psoriasis.

Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week.

Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.