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Background: Nationally, many ASCVD patients fail to achieve an LDL-C <70 mg/dL, and uptake of both statin and non-statin therapies is low. The degree to which this varies across health systems is less clear. Methods: A cross sectional analysis was performed where lipid levels and lipid lowering therapies (LLT) were assessed using electronic health record data in patients with a previous diagnosis of ASCVD. The data was obtained across 14 US healthcare systems between 1/1/2021-12/31/2022. Proportions of patients with an active prescription of any statin, high intensity statin, ezetimibe, PCSK9i, and combination therapy (two or more agents) within 395 days of the most recent LDL-C value (index date) was evaluated overall and by participating site. Additionally, the proportion of patients with an LDL-C <70 mg/dL at the index date was also assessed. Results: Across 14 health systems, 1,118,623 patients with ASCVD were identified (median 61,840 per health system, range 8,161-182,315). Overall, 675,776 (60.4%) had an LDL-C level in the past year (range 39.1% - 70.8%). Of those with a lipid level, achievement of LDL-C <70 mg/dL ranged from 34.6-47.2%. In total, 42.6% were on any statin, 20.1% were on a high intensity statin, 4.3% on ezetimibe, and 1.2% on a PCSK9i. Only 2.9% were on combination therapy of a statin with ezetimibe or a PCSK9i. Variability was seen across health systems in utilization of each of these therapies, however even in the highest performing health systems, LLT uptake and achievement of LDL-C < 70mg/dL remained low ( Figure). Conclusion: Variability in utilization of LLT in ASCVD patients between health systems suggests that system-level factors may impact achieving guideline-based LDL-C goals. Despite the variability, the highest proportion of patients achieving an LDL-C <70mg/dL remained under 50% indicating the need for aggressive implementation efforts.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure (HF) in the US today. Our prior work revealed low albumin at first hospitalization for HF exacerbation with underlying HFpEF to be an independent predictor of all-cause mortality in a small cohort of patients. We now sought to confirm our earlier findings across a larger and more diverse patient population. Methods: Seven thousand, eight hundred and forty patients had a first admission to Mayo Clinic for HF exacerbation with an echo-confirmed left ventricular ejection fraction>50% between 2010 and 2020. Patient baseline demographics, co-morbidities, admission laboratory values, echocardiographic parameters, discharge medications, and outcomes were obtained from chart abstraction. To validate our previous model, patients were grouped based on the number of risk factors as previously defined: age>80 years, serum albumin level<3.2 g/dl, medial E/e'≥20, N-terminal pro-brain natriuretic peptide (NT-proBNP) >5,000 pg/mL, and the presence of hypertension (HTN). The association with 1 year mortality was studied using Cox regression. Kaplan Meier curves were generated based on the number of factors present per patient. Results: Eleven significant univariate predictors of all-cause mortality were identified from the data (Fig. 1A), with hazard ratios (HR) ranging from 1.22-2.04 (p<0.001 for all). Notably, four previously identified prognosticators (age, albumin, medial E/e’, , HTN) were noted as significant independent predictors of all-cause mortality in HFpEF (HR 1.67, 2.14, 1.18, and 1.15, respectively, p<0.004 for all ; Fig. 1B). Multivariate regression modeling identified low albumin on presentation as being a significant adverse prognosticator (HR=2.14; p-value<0.001). Conclusion: Our analysis of 7840 HFpEF patients confirms our prior findings, suggesting that this model is a strong predictive tool for assessing the prognosis of HFpEF. Taken together, these five variables are easily available in the in-patient setting and can be incorporated into a model predictive of 1-year all-cause mortality.

Introduction: Intracellular calcium handling plays a central role in cardiac contractility and relaxation. Genes such as the Ca 2+ -ATPase pump (SERCA2a) and the Dihydropteridine reductase (DHPR) enzyme are especially important in the cycling of intracellular calcium. As prior research has established a link between treatment with our cardiac targeting peptide (CTP: a 12-amino acid, cardiomyocyte-specific cell penetrating peptide) and upregulation of calcium-handling genes such as SERCA2a and DHPR, we hypothesized that treatment with our novel hybrid cardiac targeting peptide (hCTP: positions #3 and 11 replaced with the D-enantiomer form of the amino acids) will improve intracellular calcium handling in human cardiomyocytes (CMCs) by increasing expression of key calcium handling genes instrumental in sequestering calcium in diastole and lowering cytosolic levels. Methods: To test hCTP’s calcium handling abilities, CMCs were plated on day 1 and allowed to settle for 24 hours, after which they received daily treatment with various concentrations of hCTP (1-25µM) for three days. On day 5, cells underwent either intracellular calcium measurements using the FLIPR 6 Calcium assay or were prepared for western blotting. Western blotting was performed to determine the protein concentrations of SERCA2a and DHPR, as compared to a GAPDH control. To test hCTP’s intrinsic calcium handling abilities, various concentrations of hCTP were mixed with a constant amount of elemental calcium dissolved in water. After 20 min at 37 o C, the concentration of free Ca 2+ was measured with an ABL90 Flex Plus radiometer. Results: In CMCs, treatment with hCTP led to a decrease in cytosolic calcium in a dose dependent fashion; concentrations as low as 1µM led to a significant decrease in cytosolic calcium (p< 0.0001 for all groups). Western blots performed on the treated CMCs revealed an increase in expression of both DHPR and SERCA2a, normalized to GAPDH control. Outside of the cellular environment, hCTP did not appear to display inherent calcium sequestring properties, suggesting that improvements in calcium handling are due to upregulation of gene expression. Conclusion: hCTP appears to lower cytosolic calcium and improve calcium handling through upregulation of SERCA2a and DHPR. Our data indicates that hCTP is worth pursuing as a stand-alone, cardio-selective therapy for cardiomyopathies involving calcium mishandling.

Introduction: Role of NF-κB driven inflammation leading to heart failure with preserved ejection fraction has received little attention. Our previous in vivo work with cardiac targeting peptide (CTP) in guinea pigs identified suppression of NF- κB pathway by CTP. In the current work we sought to further study the effects of a hybrid version of CTP (hCTP: amino acids at positions 3 and 11 substituted with D-amino acids) on TNF-α mediated NF-κB activation, as well as expression of its downstream inflammatory markers IL-1β and IL-8. Methods: Human cardiomyocytes (CMCs) were transfected using Lipofectamine 3000 with a reporter luciferase plasmid carrying an NF-κB promoter site upstream of the luciferase gene. Cells were treated with various concentrations of hCTP for 24 hours, followed by a TNF-α challenge (20ng/mL), addition of luciferin as substrate, and measurement of luminescence. Cell viability in response to above manipulations was assessed by FACS using live-dead stain. CMCs were treated as above, and cell culture supernatants analyzed for IL-8 levels using human ELISA kit. In another set of experiments, CMCs were transfected with NF-κB reporter plasmid, and after treatment for 24 hours with various concentrations of hCTP, incubated with 10nM angiotensin 2 (Ang2) and 100nM phenylephrine (PE) for 24hrs to assess levels of IL-1β in the cell culture media using an ELISA assay. Results: hCTP inhibited TNF-α mediated NF-κB activation with a dose-response curve, with maximum inhibition with hCTP seen at 10µM concentrations (p<0.001). Treatment with hCTP inhibited the TNF-α induced IL-8 secretion with significant decreases seen even at the 1µM dose. Similarly, secretion of IL-1β production by CMCs in response to Ang2/PE stimulation was suppressed by hCTP even at the lowest tested dose (1µM; p<0.5). Conclusions: Our data suggests that hCTP inhibited NF-κB pathway transcriptional activity in response to TNF-α stimulation in a dose-dependent fashion in human CMCs. Furthermore, treatment with hCTP inhibited TNF-α induced IL-8 and IL-1β secretion even at doses as low as 1µM. The ability of hCTP to efficiently targeting this inflammatory pathway suggests that it has therapeutic potential in the treatment of heart failure. Further in vivo studies are ongoing to test this hypothesis.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure which is rapidly rising in incidence in the US today. Despite this, no therapies with mortality benefit exist for this syndrome. Previous work with our novel hybrid cardiac targeting peptide (hCTP), a cardiomyocyte-specific cell penetrating peptide, has shown multiple beneficial biological effects (improved calcium handling, anti-inflammatory properties) beyond its transduction abilities. Therefore, we hypothesized that treatment with hCTP in a mouse model of HFpEF would ameliorate the pathophysiology of this disease. Methods: To establish a HFpEF model, 6-week-old, C57BL/6NJ mice were placed on a high-fat diet (HFD), 60% kCal from lard, and water with 0.5 g/L of an iNOS inhibitor (N-Nitro-L-arginine methylester) to induce hypertension. After 5 weeks of the diet, HFD mice and their littermate controls underwent baseline exercise testing and echocardiograms. Exercise capacity was measured after 2 days of exercise training with 2 days of rest in between; mice were placed on a treadmill at a 10-degree angle and made to run at increasingly fast speeds (5-30 m/min) until exhaustion. Echocardiograms were performed under 1.5% inhalational isoflurane. After baseline testing, the mice were treated with vehicle, or either 2.5 or 5 mg/Kg hCTP, either 3 or 5 days a week (five groups, n = 3 per group). After four weeks of treatment, the mice were again subjected to the same battery of tests and euthanized. Data was compared using two way ANOVA with Sidak’s test to compare measurements pre- and post-treatment. Results: Treatment with hCTP at either concentration for five days/week led to an increase in running distance from 39.8 m to 116.3 m (p = 0.03, n = 6), compared to changes in control distance from 208.4 m to 157.8 m (p = 0.399). Running distance did not correlate with weight (R 2 < .001). Treatment with 5 mg/Kg hCTP for 5 days/week led to a normalization of the E/e’ ratio, from 43.3 to 26.9 (p = 0.004, n = 3) compared to a change in the control of 34.7 to 26.1 (p = 0.312). Ejection fractions remained consistent (>55%) across all groups. Conclusions: Our data suggests that hCTP appears to be a promising treatment in ameliorating some of the physiological effects in a murine model of HFpEF. Gene and protein expression studies in heart tissue are underway. Further work is warranted with a larger sample size.

Background: About one in five adults at age 40 will develop heart failure (HF) during their lifetime. Risk factors for HF (e.g., hypertension, etc.) alter cardiomyocytes structure and function resulting in HF. At the cellular level, these changes consist of mis/over-expression of genes that regulate cardiac identity (e.g., CamK2d, PKC, etc). The current paradigm for treating HF is pharmacological intervention or surgery; however, with few exceptions, the condition worsens with time. We are proposing a paradigm-shift for treating HF from a drug-centric system to a molecular approach that would reverse hypertrophy and adverse remodeling. Methods: A cardiac targeting peptide (CTP) was generated and linked by disulfide bond to miRNA106a, which was then introduced into a HF mouse model to measure its ability to reverse multiple heart failure parameters. CTP-miRNA106a was also introduced into a human cardiac cell line, followed by multiple analyses including Western Blot, qPCR, FACS, immunofluorescence all used to identify mechanism(s) utilized by CTP-miRNA106a to reverse HF characteristics. Results: Bio-distribution studies showed CTP delivered its miRNA106a cargo specifically to the heart within 30 mins, followed by clearance of CTP from the heart to the kidneys and liver by 3-5hrs post systemic drug injection. MiRNA106a persisted in cardiomyocytes until day 7 (latest tested time-point). CTP-miRNA106a reversed Ang2/Iso induced hypertrophy in 90% of the experimental mice ( Fig1 ). We also identified two potential HF intracellular signaling mechanisms (PLCb1/PKC/IP3 and NfkB) targeted by CTP-miRNA106a that could benefit both types of HF, HFrEF and HFpEF. PLCβ1 is a direct target for miRNA106a while the Nfkb pathway is indirectly targeted by decreased Camk2d (an miRNA106a target) signaling to IκBα. NfkB activity is quelled by miRNA106a. Conclusions: Our approach utilizes the function of miRNA106a to downregulate genes involved in cardiac hypertrophy and inflammation through the PLCb1 and CamKIId/Nfkb pathways. Most importantly, using a CTP-miRNA106a, we show delivery of miRNA106a cargo is specific to cardiomyocytes both in vitro and in vivo and that once delivered, many HF parameters including hypertrophy are reversed.

Abstract Rationale Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality. Whether mucus plugs are associated with prospective exacerbations has not been examined extensively. Objectives To examine associations between mucus plugs on chest computed tomography (CT) and future moderate-to-severe AEs in two independent cohorts with spirometrically-confirmed COPD. Methods Mucus plugs were visually identified on baseline chest computed tomography scans from smokers with Global Initiative for Chronic Obstructive Lung Disease grade 2–4 COPD enrolled in two multicenter cohort studies: ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and COPDGene (Genetic Epidemiology of COPD). Associations between ordinal mucus plug score categories (0, 1–2, and ≥3) and prospectively ascertained AEs, defined as worsening respiratory symptoms requiring systemic steroids and/or antibiotics (moderate to severe) and/or emergency room visit or hospitalization (severe), were assessed using multivariable-adjusted zero-inflated Poisson regression; subjects were exacerbation-free at enrollment. Measurements and Main Results Among 3,250 participants in COPDGene (mean age ± SD, 63.7 ± 8.4 yr; FEV1, 50.6 ± 17.8% predicted; 45.1% female) and 1,716 participants in ECLIPSE (age, 63.3 ± 7.1 yr; FEV1, 48.3 ± 15.8% predicted; 36.2% female), 44.4% and 46.0% had mucus plugs, respectively. The incidence rates of AEs were 61.0 (COPDGene) and 125.7 (ECLIPSE) per 100 person-years. Relative to those without mucus plugs, the presence of 1–2 and ≥3 mucus plugs was associated with increased risk (adjusted rate ratio [aRR], 1.07 [95% CI, 1.05–1.09] and 1.15 [1.1–1.2] in COPDGene; aRR, 1.06 [95% CI, 1.02–1.09] and 1.12 [1.04–1.2] in ECLIPSE, respectively) for prospective moderate to severe AEs. The presence of 1–2 and ≥3 mucus plugs was also associated with increased risk for severe AEs during follow-up (aRR, 1.05 [95% CI, 1.01–1.08] and 1.09 [1.02–1.18] in COPDGene; aRR, 1.17 [95% CI, 1.07–1.27] and 1.37 [1.15–1.62] in ECLIPSE, respectively). Conclusions Computed tomography–detected mucus plugs are associated with an increased risk for future COPD AEs.

Background Optimal duration and choice of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention remain controversial. Methods and Results Digital databases (PubMed, Cochrane, and Embase) were queried to select all randomized controlled trials on a post–percutaneous coronary intervention population with acute coronary syndrome. Dual‐antiplatelet therapy (DAPT) with aspirin and clopidogrel for 12 months was compared with 4 major strategies: high‐potency, high‐ to low‐potency, low‐dose, and short‐duration DAPT. A network meta‐analysis was performed to compare the safety and efficacy of different antiplatelet strategies. This study was the second updated manuscript under the International Prospective Register of Systematic Review registration (CRD42021286552). Thirty‐two randomized controlled trials comprising 103 459 (51 750 experimental, 51 709 control) patients were included. Compared with DAPT with aspirin and clopidogrel for 12 months, high‐ to low‐potency DAPT (risk ratio [RR], 0.69 [95% CI, 0.52–0.92]) and aspirin+prasugrel containing DAPT for 12 months (RR, 0.84 [95% CI, 0.72–0.98]) had a significantly lower, whereas DAPT for 1 month followed by clopidogrel only (RR, 1.59 [95% CI, 1.06–2.39]) had a higher, incidence of major adverse cardiovascular events at 1 year (median follow‐up). Prasugrel (RR, 1.35 [95% CI, 1.09–1.66]) and ticagrelor (RR, 1.38 [95% CI, 1.17–1.62]) containing DAPT for 12 months had significantly higher rates, whereas high‐ to low‐potency DAPT (RR, 0.85 [95% CI, 0.63–1.15]) had no significant risk of major bleeding. Conclusions Aspirin and ticagrelor for 3 months, followed by aspirin and clopidogrel for the remaining duration, can be considered the optimal strategy for treating post–percutaneous coronary intervention patients with acute coronary syndrome because of a significantly reduced risk of major adverse cardiovascular events without increasing the risk of bleeding.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P &lt; 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P &lt; 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P &lt; 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P &lt; 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P &lt; 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

One of the bottlenecks to bringing new therapies to the clinic has been a lack of vectors for delivering novel therapeutics in a targeted manner. Cell penetrating peptides (CPPs) have received a lot of attention and have been the subject of numerous developments since their identification nearly three decades ago. Known for their transduction abilities, they have generally been considered inert vectors. In this review, we present a schema for their classification, highlight what is known about their mechanism of transduction, and outline the existing literature as well as our own experience, vis a vis the intrinsic anti-inflammatory properties that certain CPPs exhibit. Given the inflammatory responses associated with viral vectors, CPPs represent a viable alternative to such vectors; furthermore, the anti-inflammatory properties of CPPs, mostly through inhibition of the NF-κB pathway, are encouraging. Much more work in relevant animal models, toxicity studies in large animal models, and ultimately human trials are needed before their potential is fully realized.