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Background: Recurrent pericarditis results from inflammasome activation and is associated with significant morbidity. Cannabidiol has been shown to block numerous inflammasome signaling pathways, including reducing transcription of pro-IL-1β and NLRP3, and inhibiting secretion of IL-1β and IL-6. Aim: To assess the impact of oral pharmaceutically manufactured (P-)cannabidiol in recurrent pericarditis patients (pts). Methods: Adult pts (≥18 years) with symptomatic, recurrent pericarditis (≥2 recurrences) were eligible for this open-label, multicenter study. Eligible pts had pericarditis chest pain with a numerical rating scale (NRS) pain score ≥4 within 7 days prior to enrollment, together with either elevated (≥1.0 mg/dL) C-reactive protein (CRP) within the prior 7 days or prior pericardial late gadolinium enhancement (LGE) on cardiac imaging. Pts had to be on chronic treatment with NSAIDs, colchicine or corticosteroids (any combination) with stable baseline (BL) doses. Oral P-cannabidiol was uptitrated to 10 mg/kg twice daily (BID), or maximum tolerated dose. The primary efficacy endpoint was improvement in NRS pain score at week 8 (WK8). A secondary efficacy endpoint among pts with elevated BL CRP was the percentage of pts with CRP normalization (≤0.5 mg/dL) at WK8. Results: 27 pts, mean age of 53 years (range 24-77), 18 of female sex, with a median of 3 prior pericarditis episodes were enrolled. CRP was ≥1.0 mg/dL in 10 pts (37%) at BL. Prior evidence of LGE was present in 21 pts (78%). At BL, 41% of pts were receiving corticosteroid therapy. The highest tolerated study medication dose was BID 10 mg/kg in 20 pts (74.1%), 7.5 mg/kg in 4 pts (14.8%), and 5 mg/kg in 3 pts (11.1%). All 27 pts (100%) completed the WK8 visit. Mean NRS score decreased by 3.7, from 5.8 at BL to 2.1 at WK8. In those with CRP elevation at BL, CRP normalized in 8 pts (80%) by WK8, with mean CRP decreasing from 5.71 to 0.31 mg/dL. Study medication was discontinued due to AEs in 2 pts (7.4%). 24 pts (89%) tolerated P-cannabidiol with a treatment response and proceeded into the 18-week extension period (EP) where background therapy is weaned. Conclusions: Among pts with symptomatic pericarditis recurrence, oral administration of P-cannabidiol led to a clinically relevant reduction in pericarditis chest pain (measured by NRS score) and in CRP. P-cannabidiol was shown to be safe and generally well tolerated, with the majority of pts reaching the target dose and continuing into the study EP.

Introduction: Menopause is known to be associated with myocardial infarction (MI). However, the association between menopause age and MI onset in a nationally representative population remains unknown. Objective: To examine the correlation between age of menopause and age of MI onset in the general population and the association between early menopause (onset of menopause ≤ 40 years old) and early onset of MI (onset of MI ≤ 40 years old). Methods: A cross-sectional study was conducted using a population from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). The questionnaire collected self-reported data on the participants' menopause age and their age of first MI. The relationship between these two parameters was analyzed by multivariate linear and logistic regression analyses. Multivariate analysis was adjusted for race, age, body mass index (BMI), smoking status, diabetes mellitus (DM), hypertension, and dyslipidemia status. Results: Among 2,200 postmenopausal females, 90 (4.1%) have had MI. The study involved 85 postmenopausal females who reported both menopause age and MI onset, with a mean ± SD age of 55 ± 13 years. This study found a significant association between menopause age and MI onset. After adjusting for confounders, it was found that every 1-year increase in the age of menopause will delay the onset of MI by 0.28 years, with a 95% CI of 0.013 to 0.552 (Table 1A, Graph 1A, Graph 1B). Additionally, early menopause carries an almost significantly increased risk of 2.11 times (95% CI: 1.00, 4.45) for early-onset MI. After adjusting for confounders, the magnitude of the association was lower and not statistically significant, but the direction remains (OR (95% CI): 2.08 (0.87, 4.95)). However, after stratification with comorbidities, DM status was identified as an effect modifier, with early MI significantly observed in patients with DM in both univariate and multivariate analyses, with OR (95% CI) of 3.03 (1.10, 8.37) and 4.88 (1.26, 18.96), respectively (Table 2A). Conclusion: This study demonstrated a positive association between menopause age and MI onset in a generally representative population. This suggests that prolonged estrogen exposure due to late menopause may delay the onset of MI. Additionally, early menopause was associated with early MI onset in the DM population. Further longitudinal studies are required to examine the potential mechanisms involved in menopause onset and MI onset.

Background: Radial artery (RA) access has become common in cardiac catheterization due to fewer vascular complications and MACE compared to transfemoral approach (TFA). However, anatomic variations are more profound in the upper-extremity. Research Question: What are common anatomic variations encountered during transradial approach (TRA) coronary angiography and what association do they have with adverse outcomes and procedural challenges? Methods: We performed a single-center retrospective analysis of 926 patients who underwent coronary angiography through TRA via the right upper-extremity where RA angiogram was performed from 01/2010 to 01/2023. Multivariate logistic regression was utilized to estimate the odds ratio (OR) of the association between anatomic variations and adverse outcomes and procedural challenges. Results: A total of 926 patients with a mean age of 59.9 years were studied with 30.4% being female. Common comorbidities were HTN (82.2%), HLD (51.8%), and DM (45%). About 32% of patients had an anatomic variation. Prevalences were 14.4% radial tortuosity, 12% high RA bifurcation, 11.9% M-sign, and 1% RA loops. These patients were older (P<0.001) and more likely to have HLD (P=0.049). They had high odds of high contrast dose (OR 1.73; 95% CI 1.28-2.34, P<0.001), long fluoroscopy time (OR 2.02; 95% CI 1.50-2.73, P<0.001), high radiation exposure (OR 2.47; 95% CI 1.79-3.42, P<0.001), difficulty engaging coronary arteries (OR 2.70; 95% CI 1.94-3.74, P<0.001), and transfer to TFA (OR 4.89; 95% CI 2.36-10.12, P<0.001). Females (OR 2.89; 95% CI 2.01-4.15, P<0.001), small RA size (OR 2.61; 95% CI 1.76-3.86, P<0.001), high RA bifurcation (OR 1.68; 95% CI 1.02-2.75, P=0.04), and M-sign (OR 2.04; 95% CI 1.24-3.35, P=0.005) were associated with RA spasm. Major complications were not significant. Conclusion: We found a high prevalence of anatomic variations. They were associated with high odds of adverse outcomes and procedural challenges during TRA coronary angiography.

Introduction: Stroke-related mortality poses significant challenges in the US. Increased at-home deaths since COVID-19 pandemic prompted changes in the provision of end-of-life care. Question: What were the settings of stroke deaths in the US during COVID-19 pandemic? Methods: Decedent-level mortality data from death certificates in CDC repository were obtained for the year 2020 (pandemic) and 2019 (comparison). Demographic data include age, sex, race/ethnicity, education, marital status, and place of stroke death, including inpatient, outpatient/emergency room (ER), hospice/nursing facilities (H/NF), and at-home. Multivariable logistic regression models assessed demographic impact on stroke mortality by place-of-death, yielding odds ratios (OR) with significance threshold of p<0.05. Results: A total of 5,400 and 5,712 stroke-related deaths occurred in 2019 and 2020, respectively. During COVID-19, decedents >65 years were more likely to die in H/NF (OR 10.05, p<0.001) but less likely in outpatient/ER (OR 0.32, p<0.001) or at home (OR 0.57, p=0.007) compared to those <35 years. High education level did not significantly influence the place of death than having high school diploma or less (p>0.05). Males were more likely to die at home (OR 1.38, p<0.001) but less likely as inpatient (OR 0.79, p<0.001) than females. Hispanic decedents had a higher likelihood of inpatient death (OR 1.22, p=0.041) but less likely to die in H/NF (OR 0.55, p<0.001) compared to non-Hispanic decedents. Compared to White decedents, Black decedents were more likely to die in outpatient/ER (OR 1.44, p=0.018), while American Indian decedents were more likely to die as inpatient (OR 3.12, p=0.005). Asian/Pacific Islander decedents had a higher chance of inpatient death (OR 1.47, p=0.002) but a lower likelihood of dying in H/NF (OR 0.61, p=0.010). Married decedents were more likely than singles to die as inpatient (OR 1.37, p=0.001) or in outpatient/ER (OR 1.99, p<0.001), but less likely to die in H/NF (OR 0.61, p=0.002) or at home (OR 0.56, p<0.001). Conclusion: Our analysis revealed the influence of demographics on the settings of stroke fatalities during the COVID-19 pandemic. Further investigation is needed to determine contributing factors.

BACKGROUND: Atrial natriuretic peptide (ANP) and glucagon-like peptide-1 (GLP-1) are endogenous hormones known for roles in cardiovascular regulation and metabolic homeostasis. ANP mediates its actions via the GC-A receptor, while GLP-1 via the GLP-1 receptor (GLP-1R). Both peptides may stimulate insulin secretion from pancreatic beta cells and augment lipid metabolism in adipocytes, yet potential synergistic effects remain unexplored. To optimize ANP activation of GC-A, we developed a novel 15 amino acid miniaturized GC-A activating peptide CRRL555. CRRL555 possesses greater GC-A binding and activating properties than ANP. AIMS: We investigated the metabolic properties of CRRL555/GC-A and its interaction with GLP-1/GLP-1R in vitro. METHODS: Rat pancreatic beta cells (INS-1) were stimulated with high glucose (20mM) and treated with GLP-1 or CRRL555 (10 -10 -10 -6 M) and together for 1 hr. Supernatant was collected and insulin was measured by ELISA. Human visceral adipocytes were differentiated for 10 days and then treated with GLP-1 or CRRL555 (10 -10 -10 -6 M) or together for 6 hrs. Supernatant was collected and glycerol and free fatty acid (NEFA), indicators of lipolysis, were measured. RESULTS: CRRL555 (p<0.05) and GLP-1 (p<0.05), dose dependently, stimulated insulin secretion in INS-1 cells in the presence of high glucose. Importantly, CRRL555 combined with GLP-1, resulted in a greater enhancement (p<0.05) of insulin secretion compared to either peptide alone. While high dose CRRL555 and GLP-1 (10 -6 M) stimulated lipolysis in visceral adipocytes with increases in glycerol and NEFA, only CRRL555 at low dose (10 -10 M), and not low dose GLP-1 (10 -10 M), stimulated glycerol and NEFA production (p<0.05). When low dose GLP-1 (10 -10 M) was added to low dose CRRL555(10 -10 M), lipolysis was like CRRL555 alone. CONCLUSION: We report a novel synergy in insulin release from beta cells with combined stimulation of the potent and miniaturized GC-A designer peptide CRRL555 with GLP-1. CRRL555 possesses greater lipolytic properties compared to GLP-1 in visceral adipocytes at low doses advancing novel metabolic actions of CRRL555 alone or combined with GLP-1R activation. These in vitro studies of dual receptor activation of GC-A and GLP-1R highlight the therapeutic potential of combining CRRL555 with GLP-1-based therapies for the treatment of cardiometabolic diseases, thus supporting studies of dual GC-A/GLP-1R activation in experimental cardiometabolic disease states.

Background: Right ventricular pacing (RVP) can have adverse cardiac effects and cause pacing induced cardiomyopathy (PiCM). His bundle pacing (HBP)&Left Bundle Branch area pacing (LBBAP) mimic physiologic conduction (PhysioP) and maintain biventricular synchrony. Hypothesis and Aims: Reduced left ventricular (LV) systolic function reserve in the presence of normal baseline LV ejection fraction (EF) could precede development of RV PiCM. Our aim was to compare the effects of RVP vs. PhysioP on bicycle exercise cardiopulmonary performance in patients with normal LVEF who required pacing for bradyarrhythmias. Methods: Patients with sinus rhythm and RVP or PhysioP&ventricular pacing burden of >70% who completed cardiopulmonary exercise test and simultaneous stress echocardiography (SE) were included. Pulmonary gas exchange was calculated using Ventilation/CO2 production at rest and during exercise. Changes in LV size, EF, longitudinal strain and diastolic function and gas exchange parameters were compared post and pre exercise in the 2 groups. Results: 25 of 29 patients completed the study [68 ± 23 yrs, 48% M; LVEF 56±5%, 11 RVP, 14 PhysioP]. There was no difference in baseline demographic&clinical variables, exercise duration, rest and peak heart rate and blood pressure between 2 groups. Pacing duration was 2.61±1.48 yrs in RVP vs. 0.84±0.67 yrs (p=0.003) in the Physio group. Resting echocardiographic parameters ( Table 1A) were comparable. Compared to RVP, reduction in LV end-diastolic volume (EDV) 3.4±14.1 ml vs. -23.1±18.1ml, p=0.006)&LV end-systolic volume (ESV -5.7±11.6 ml vs. -18.0±9.5ml, p=0.01) was more pronounced in the PhysioP group. Changes in LVEF, LV strain&diastolic function were not different between the 2 groups ( Table 1B ). There were no significant differences in changes in pulmonary gas exchange parameters in the 2 groups. Conclusions: In patients with normal LVEF and pacemaker dependent, RVP is associated with impaired but PhysioP with preserved LV systolic function reserve, which can be detected by exercise SE. SE may help identify patients at risk for RV PiCM. Benefit of PhysioP needs to be determined by larger studies with longer follow-up.

Background: We identified a novel, ultra-rare missense variant (p.R534S) in DENND3 as a potential disease-susceptibility variant in a multi-generational pedigree of familial idiopathic ventricular fibrillation (IVF). DENND3 is a guanine nucleotide exchange factor and activator for small GTPase Rab proteins involved in endosome and ion channel membrane trafficking. However, the role of DENND3 in the heart and its potential involvement in cardiac arrhythmias are unknown. Objective: To functionally characterize DENND3-p.R534S and determine its impact on channel trafficking. Methods: Heterologous co-expression studies in TSA201 cells were performed with DENND3-WT or DENND3-p.R534S and ion channels: KCNQ1 (Kv7.1, IKs), KCNH2 (Kv11.1, IKr), SCN5A (Nav1.5, INa), or CACNA1C (Cav1.2, ICa) as well as Rab proteins (Rab4, Rab5, Rab6, Rab7, Rab11, Rab12). Patient-specific DENND3-p.R534S iPSC-derived cardiomyocytes (iPSC-CMs) and isogenic controls (IC) were created. Localization and expression of ion channel and Rab proteins was assessed using immunofluorescence (IF) by super resolution AiryScan microscopy. GTPase-Glo assays measured Rab protein activity. Electrophysiology studies using patch-clamp and FluoVolt were performed on iPSC-CM models. Results: IF imaging showed significant increases in membrane expression of KCNQ1 (11714±157to 21929±378, p<0.05), KCNH2 (11378±160 to 31965±544, p<0.05), , SCN5A (10339±8 to 11225±23, p<0.05), and CACNA1C (11879±83 to 13749±138, p<0.05) in DENND3-p.R534S compared to DENND3-WT expressing TSA201 cells. Rab5 distribution was altered significantly by the DENND3-p.R534S variant, with increased dispersion away from the nucleus (0.23±0.01 vs. 0.17±0.01, p<0.05) and increased proximity to the plasma membrane (0.16±0.02 vs. 0.23±0.01, p<0.05). Additionally, Rab5 activity was enhanced significantly (57% increase) by p.R534S versus WT (p<0.05). iPSC-CMs revealed similar increases in channel membrane accumulation and irregular arrhythmic activity including frequent action potential duration alternans and afterdepolarizations in 78% of p.R534S iPSC-CMs versus none in IC cells (p<0.05). Conclusion: DENND3 is a novel ion channel trafficking protein in the heart. The DENND3-p.R534S variant disrupts cardiac ion channel trafficking. These findings highlight DENND3’s role in cardiac ion channel distribution, cellular function, and potential association with arrhythmogenic risk.

Background: Cardiac channelopathies are a heterogenous group of genetic heart diseases (GHDs) that affect cardiac ion channel function. The most prevalent among these are long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) which predispose patients to potentially life threatening ventricular arrhythmias. Accurate and timely diagnosis is important for the management and risk stratification of the index case and identification of potentially at-risk relatives. Unfortunately, despite rising awareness of these GHDs, critical warning signs are overlooked. Objective: To describe the phenotypes of patients who present with a delayed or missed diagnosis of LQTS or CPVT. Methods: EMR data was reviewed for all patients evaluated and treated at Mayo Clinic between 2000-2023 who arrived with a mis- or delayed diagnosis of LQTS or CPVT. Data was abstracted for patient demographics, clinical characteristics, family history of SCD, and cardiac and genetic test results. Results: Overall, 47/2119 (2%) patients [33 (70%) female, mean age at correct diagnosis 26±18 years] diagnosed with LQTS (30; 2% of LQTS cohort) or CPVT (17; 7% of CPVT cohort) arrived with an outside misdiagnosis (37, 79%) or underdiagnosis (10, 21%). The most common misdiagnosis was epilepsy (20; 43%) or vasovagal syncope (14; 30%) and 3 CPVT patients (6%) were misdiagnosed with LQTS. Of the 10 underdiagnosed patients, 4 (40%) had QT prolongation, 4 (40%) family history of SCD, 3 (30%) bilateral deafness, and 1 (10%) fetal bradycardia and syndactyly. Overall, 40/47 (85%) were symptomatic (syncope: 29 [73%], seizures: 21 [53%], SCA: 10 [25%]) prior to diagnosis. Of note, 34/40 (85%) had symptoms with exertion, 5 (13%) at rest, and trigger was unknown in 1 (2%). Of the 7 asymptomatic patients (15%), 4 (57%) had QT prolongation and 4 (57%) had family history of SCD. In total, 20/47 patients (43%) had positive family history of SCD under 45 years of age. Overall, patients experienced a median delay in diagnosis of 8 years during which a median of 4 events (range: 1-150) occurred. As a result, an additional 29 family members of these patients received a delay in their diagnosis. Conclusions: Recognizing the signs and symptoms of patients with GHDs is important to reduce the ongoing burden of misdiagnosis or delayed diagnosis in LQTS and CPVT. The most important factors for suspicion of an inherited channelopathy are symptoms during exertion and family history of SCD.

Background: CDCP1 has been associated with reverse remodeling in human dilated cardiomyopathy (DCM) mediating its effect by reducing cardiac fibrosis which has been demonstrated in-vitro using human cardiac fibroblasts (CF) and in-vivo histologically in mice. However, the role of and the molecular mechanisms by which CDCP1 attenuates cardiac fibrosis in-vivo is unknown. Methods: To characterize the transcriptomic profiles of CDCP1 in cardiac fibrosis, Cdcp1 KO FVB/NJ mice were generated, and implanted with osmotic minipumps containing angiotensin II and phenylephrine (Ang II/PE) or saline at age of 10 weeks. There were 4 experimental groups (6 mice each), Saline_WT, Saline_KO, AngII/PE_WT, and AngII/PE_KO. After 4 weeks of AngII/PE induction, mice were euthanized, RNA was extracted from their heart tissue followed by RNA-seq to explore transcriptomic profiles. Fibrosis was histologically determined using picosirius (PSR) staining and was quantified by percentage of fibrosis area. Results: Histological analysis demonstrated that Cdcp1 KO attenuated severe cardiac fibrosis by 32.7% determined by quantification of percentage of fibrosis area. When comparing the transcriptome-wide gene expression in WT mice hearts from Saline to AngII/PE induction, a total of 316 differentially expressed genes (DEGs) were identified ( Fig. 1A ). Expression of Nppb (encodes ProBNP), a marker for heart failure, was significantly upregulated. The most significantly upregulated DEG after AngII/PE induction was Crlf1 ( Fig. 1A ), a gene predominantly expressed in CF, consistent with previous findings. We next compared transcriptomic profiles of AngII/PE induction WT and Cdcp1 KO mice hearts, to explore the role of CDCP1 in cardiac fibrosis. A total of 163 DEGs were identified ( Fig. 1B ). Notably, Cdcp1 -mediated DEGs enriched GO Pathways associated with extracellular matrix organization (Biological Process) and collagen-containing extracellular matrix (Cellular Component) ( Figs. 1C, 1D ), pivotal processes in cardiac fibrosis. In addition, Cdcp1 KO resulted in several “top” DEGs (including Rnase1, Ccl7, Ccl12 Il21r , and Il6 ) which have known function in inflammation, suggesting that CDCP1 might attenuate cardiac fibrosis through immune regulation . Conclusion: Our findings underscore the pivotal role of CDCP1 in modulating cardiac fibrosis in-vivo, potentially through immune regulation. Targeting CDCP1 may offer promising therapeutic avenues for mitigating myocardial fibrosis.

Background: Papillary fibroelastomas (PFE) arising between the left upper pulmonary vein and left atrial appendage, commonly referred to as the coumadin ridge or Q-tip, are extremely rare and best detected by transesophageal echocardiography (TEE). Although PFEs are benign, they have been associated with a range of serious embolic events. Objective: To analyze the characteristics, clinical findings, and diagnostic techniques of PFEs originating from the coumadin ridge. Methods: We describe 13 cases of pathology proven papillary fibroelastomas uniquely attached to the Q-tip. Patient data, including demographics, mass characteristics and diagnostic imaging were collected and analyzed. Results: Thirteen patients with pathology-proven PFEs attached to the coumadin ridge were included in the study. The median age of the cohort is 73 (IQR 67-77), and 54% of the patients were male. Tumor sizes ranged from 2mm to 20mm with a median of 5mm (IQR 3.5-8.5). Twelve (92%) of the PFEs were initially visualized on TEE, and one case was diagnosed postoperatively by pathologists after the excision of the left atrial appendage. The majority of cases were incidental diagnoses, with 46% of cases incidentally discovered intraoperatively by routine TEE, and 30% visualized on TEE done for diverse reasons including valvular assessment, exclusion of infective endocarditis, and coronary artery disease (CAD) assessment. One case was incidentally detected on CMR performed as part of a metastatic tumor workup. Four (30%) patients presented with symptoms of stroke/TIA, of which 2 had a previous history of stroke. One patient had symptoms of both TIA and angina pectoris. Cardiovascular disease risk factors were prevalent: 69% had hyperlipidemia, 46% had atrial fibrillation (Afib), 31% had CAD, 54% had hypertension, and 46% were former smokers. Conclusions: Masses on the Q-tip are rare but significant intracardiac sources of embolism. Accurate identification and categorization of these masses are challenging, yet critical, to guide appropriate surgical intervention and improve patient outcomes. Further studies are needed to establish standardized diagnostic and treatment protocols for this unique presentation of PFEs.