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Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Prior studies have demonstrated abnormalities of diastolic function are independent predictors of heart failure and all-cause mortality. The optimal way to classify diastolic function has continued to evolve over time, particularly in those with preserved left ventricular ejection fraction. A notable change in the 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) guidelines is that individuals with impaired myocardial relaxation and normal filling pressure can be classified as normal diastolic function. Purpose To determine whether the association of diastolic dysfunction with increased risk of all-cause mortality is driven by cardiovascular or non-cardiovascular death. Second, to evaluate if the presence of an impaired myocardial relaxation inflow pattern without other diastolic abnormalities conveys a marker of increased risk. Methods This study utilized the Olmsted County Heart Function Study (OCHFS), a well characterized prospective adult community cohort with comprehensive echocardiography between 2001 and 2004 and long-term follow-up. Only individuals with measurable diastolic function were included (n = 1,104). Those with reduced left ventricular ejection fraction, more than moderate valve disease, or a clinical diagnosis of heart failure (n = 52); or indeterminate diastolic function (n = 47) were excluded. Diastolic function was assessed by the current Mayo Clinic diagnostic algorithm (Figure). Results A total of 695 individuals were classified as normal, 265 with impaired myocardial relaxation or grade 1 diastolic dysfunction, and 45 with grade 2-3 diastolic dysfunction. Those with diastolic dysfunction were older and had more comorbidities including diabetes, hypertension and coronary disease (Table). There were 264 deaths in the median follow up period of 15.2 years (IQR 14.4 – 18.0), including 173 non-cardiovascular and 81 cardiovascular deaths. Both cardiovascular and non-cardiovascular mortality were associated with the presence and grade of diastolic dysfunction (Table 1). Individuals classified as normal by 2016 ASE/EACVI criteria, but grade 1 by the Mayo algorithm had an increased risk of all-cause mortality after univariate analysis (HR 4.35, 95% CI (3.35, 5.65), p < 0.0001) compared to normal subjects and remained associated after adjustment for age (HR 1.55, 95% CI (1.15, 2.09), p < 0.0001. Subjects with a grade 1 pattern had a higher rate of cardiovascular mortality (ꭕ2 70.1, p < 0.0001). Conclusions Individuals with diastolic dysfunction, including those with an impaired relaxation mitral inflow, were at increased risk of mortality, particularly cardiovascular mortality. This study highlights the importance of separating grade 1 diastolic dysfunction from normal in the assessment of diastolic function as it represents a clinically significant risk marker of myocardial disease. Abstract Figure. Abstract Figure.

Abstract Funding Acknowledgements Type of funding sources: None. Background Pulmonary hypertension (PH) is a progressive pulmonary vascular disorder with an elevated mortality risk due to right ventricular failure. Pulmonary arterial pulsatility index (PAPi) based on invasively acquired parameters has emerged as a potentially valuable hemodynamic risk predictor. Whether non-invasively derived PAPi (PA pulse pressure/ RA pressure) is valuable is unclear. Purpose To assess whether PAPi measured non-invasively by transthoracic echocardiography acts as a prognostic hemodynamic biomarker of patient risk. Methods Consecutive patients undergoing transthoracic echocardiography for known or suspected PH over a one year period were included. PA systolic and diastolic pressure were estimated in standard fashion from peak tricuspid and end-pulmonary regurgitant Doppler profiles. Right atrial pressure was estimated based on 2D & Doppler assessment of the inferior vena cava hepatic vein. In those patients with PH (mean PA pressure > 20 mm Hg), PAPi was divided into 3 groups based on prior publications with invasive data as <1.5, 1.5 to 3 and >3. Mortality was assessed over 5 years. Results Of 1,045 patients enrolled 64% had PH. Patients with the lowest PAPi (table) had higher NT-proBNP levels, larger right ventricles, worse right heart systolic function (cardiac output, TAPSE, systolic annular velocity, free wall systolic strain) and greater degrees of tricuspid regurgitation (Table). In patients with PH, PAPi was inversely associated with death (figure, p < 0.0001) with each group of PAPi correlating with incrementally worse survival. Patients with a PAPi of <1.5 had worst right heart size and dysfunction on echo (table) and worst survival (figure). Conclusions In patients with PH, low PAPi derived non-invasively by transthoracic echocardiography is associated with markers of right heart failure, right ventricular dysfunction and worse survival. PAPi could be incorporated into the conventional echo parameters reported in patients with known or suspected PH and maybe a useful predictor of outcome. Abstract Table Abstract Figure

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) is known to cause dilation in both the mitral (MA) and the tricuspid (TA) annuli. Few studies have investigated MA dynamics and function in AF compared to sinus rhythm (SR). However, no study addressed this issue in TA. Hence, we set forth to describe TA dynamics in AF and SR and its relationship with severity of tricuspid regurgitation (TR). Methods 3D echocardiographic imaging data were acquired from adult patients in AF or SR with varying degrees of TR between 2018 and 2020. TA was automatically tracked throughout the cardiac cycle using a commercially available software (TomTec 4MV software; Figure 1) over 4-6 cardiac cycles per patient. Time to minimal area as percentage of the R-R interval was recorded in each of the cycles. Absolute change in TA area was calculated as the difference between maximal and minimal TA area in each cardiac cycle and was averaged over 4-6 cycles per patient. This measurement was used to reflect the dynamic range of TA deformation during the cardiac cycle. Right atrial (RA) and right ventricular (RV) volumes and longitudinal strain were also measured (speckle tracking, 4-ch view). Results A total of 70 patients were studied (35 AF; 35 SR; 54% males in each group). Patients with AF were older [median (IQR) of 81 (72-86) years vs. 69 (59-78) years in SR, p < 0.001], had larger maximal TA area and circumference (p < 0.001 for both), larger RA size (p < 0.001), lower RA reservoir strain (p < 0.001) and RV free-wall strain (p < 0.001). Absolute change in TA area was significantly decreased in AF [2.3 (1.7-2.7) cm2] vs. 3.1 (2.3-3.5) cm2 in SR, p = 0.002. Patients with ≥ moderate TR (n = 41, 59%) had lower absolute change in TA area [2.4 (1.7-3.1) cm2 vs. 2.8 (2.2-3.5) cm2 in < moderate TR, p = 0.05]. Female sex was associated with lower absolute change in TA area [2.3 (1.7-3.2) cm2 vs. 2.7 (2.2-3.6) cm2 in males, p = 0.02] on univariate analysis. AF patients had more frequently ≥ moderate TR [28 AF vs. 13 SR, p < 0.001]. On multivariate analysis including sex, rhythm, TR severity, RA and RV strains, and averaged maximal TA area, independent factors associated with lower absolute change in TA area were AF, ≥ moderate TR, and larger maximal TA area (p < 0.05 for all). Time to minimal TA size was achieved in (0-40%) of the R-R interval in 70% of patients in SR compared to only 41% of patients in AF (Figure 2) and in 73% in patients with < moderate TR compared to 43% in patients with ≥ moderate TR. Conclusion AF is associated with blunted TA dynamics resulting in lower decrease in TA size and with a heterogenous timing of minimal TA size throughout the cardiac cycle. The blunted and discoordinated annular contraction may reduce systolic tricuspid valve competence and be involved in the pathophysiology of functional TR. Future studies are needed to confirm this hypothesis and evaluate the effect of restoration of SR on TA dynamics and time to minimal TA size. Abstract Figure 1Abstract Figure 2

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction: Transesophageal echocardiography (TEE) has long provided excellent diagnostic imaging of left-sided valvular pathology with an excellent safety profile; however, recent data has suggested an increased risk of injury related to TEE guidance. Purpose This study aims to evaluate the incidence and nature of TEE-related oropharyngeal or esophageal complications in patients undergoing TEE-guided structural heart procedures and identify associated risk factors. Methods We reviewed consecutive patients undergoing TEE-guided structural heart procedures from 2005-2020. All procedures were performed under general anesthesia. TEE-related oropharyngeal or esophageal complications were defined as those occurring within 30 days of the procedure resulting in i) persistent dysphagia, odynophagia, or upper gastrointestinal bleeding requiring prolonged endotracheal intubation, therapeutic endoscopic or surgical intervention, or diagnostic imaging that demonstrated oropharyngeal or esophageal injury. ii) upper gastrointestinal bleed requiring transfusion, hemodynamic compromise warranting mechanical or pharmacologic support; or iii) oropharyngeal or esophageal complications leading to death. For multivariate analysis, all variables with a p < 0.15 at univariate analysis were included in the model. Results Among 1229 adult patients undergoing TEE-guided structural heart procedures between 2005-2020, 274 underwent a transcatheter aortic valve replacement (TAVR) with the remaining 955 undergoing either mitral valve transcatheter edge-to-edge repair (mTEER, n = 278), mitral paravalvular leak closure (PVLC, n = 354), mitral valve-in-valve replacement (VIV, n = 41), or left atrial appendage closure (LAAO, n = 282). Of these, 6 (0.5 %) had TEE-related complications; 0% TAVR, 0% VIV, 0.36% LAAO, 0.28% PVLC, 1.41% mTEER (p = 0.14). Of the six patients with complications 3 required at least one day of prolonged tracheal intubation and one a blood transfusion. None required surgical repair. Factors associated with increased complication risk (Table) included a prior history of gastrointestinal bleed (Odds ratio 5.44 [0.98-30.04; p = 0.05]) and longer procedural time (OR per 30 min 1.15 [1.01-1.31, p = 0.03]). Patients undergoing mTEER had an increased risk of complication (OR 6.76 [1.23-37.1 p = 0.03]) and longer procedural time (OR per 30 mins 1.15[1.01-1.31, p = 0.04]) compared to other all other procedures. Conclusion(s): In a large series of patients undergoing cardiac structural interventions under general anesthesia with TEE-guidance, rates of TEE-induced injury were low. Risk of oropharyngeal or esophageal complications was increased with longer procedure times, prior gastrointestinal bleeding history, increased age, increased pre-procedural creatinine, procedural type being mTEER and in male patients, lower height. Abstract Table

Abstract Funding Acknowledgements Type of funding sources: None. Background Tricuspid regurgitation (TR) is a prevalent valvular lesion with three broad morphologic subtypes: primary due to intrinsic pathology of the valve or subvalvular apparatus; secondary due to pulmonary hypertension; and isolated TR associated with chronic atrial fibrillation. The complex pathophysiological, clinical and echocardiographic features between these subtypes require further investigation. Purpose We aimed to identify the different phenotypes of TR using cluster analysis, and determine differences (if present) in clinical outcomes associated with these phenotypes. Methods We included 13611 patients with ≥ moderate TR, either primary or secondary, in the final analyses. The demographic, clinical and echocardiographic data of these patients were evaluated using Ward’s minimum variance cluster analysis including a total of 38 variables. Survival analysis for all-cause mortality was performed using the Kaplan-Meier method, and groups were compared using the log-rank test. Results The mean age of patients was 72.5 ± 13.4 years, 7590 (56%) were females. The clustering identified 5 distinct phenotypes. Cluster 1 represented "low-risk TR" with lesser severity likely related to chronic atrial fibrillation. This cluster had less severe TR, normal sized right ventricle and fewer comorbidities. Clusters 2-5 represented "higher severity TR", "TR associated with lung disease", "TR associated with coronary artery disease and ischemic cardiomyopathy" and "TR associated with chronic kidney disease" respectively (Figure 1). Cluster 1 had the best overall survival, followed by clusters 2, 3 and 4, and lastly cluster 5, with the worst outcome (Figure 2). Conclusions Cluster analysis identifies 5 phenotypically distinct novel subgroups of TR with differences in all-cause mortality. This phenotype-based classification improves our understanding of interaction of different co-morbidities with this complex valve lesion and can inform clinical decision making. Abstract Figure. Cluster Dendrogram Abstract Figure. Kaplan-Meier survival curves

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by inflammatory flares of soft tissues, leading to heterotopic ossification and significant cumulative morbidity and early mortality. FOP minor trauma, including intramuscular medication administration, can induce ossification and should be avoided. We present a case of known FOP in a patient who presented with fevers of unknown origin and was found to have biopsy-proven ileal Crohn's disease. Crohn's disease management was complicated by concerns that intramuscular therapies would induce ossification, and oral monotherapy with methotrexate was initiated with excellent results.

Abstract This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Abstract Background Galectins have numerous cellular functions in immunity and inflammation. Short-term galectin-2 (Gal-2) blockade in ischemia-induced arteriogenesis shifts macrophages to an anti-inflammatory phenotype and improves perfusion. Gal-2 may also affect other macrophage-related cardiovascular diseases. Objectives This study aims to elucidate the effects of Gal-2 inhibition in atherosclerosis. Methods ApoE −/− mice were given a high-cholesterol diet (HCD) for 12 weeks. After 6 weeks of HCD, intermediate atherosclerotic plaques were present. To study the effects of anti-Gal-2 nanobody treatment on the progression of existing atherosclerosis, treatment with two llama-derived anti-Gal-2 nanobodies (clones 2H8 and 2C10), or vehicle was given for the remaining 6 weeks. Results Gal-2 inhibition reduced the progression of existing atherosclerosis. Atherosclerotic plaque area in the aortic root was decreased, especially so in mice treated with 2C10 nanobodies. This clone showed reduced atherosclerosis severity as reflected by a decrease in fibrous cap atheromas in addition to decreases in plaque size.The number of plaque resident macrophages was unchanged; however, there was a significant increase in the fraction of CD206+ macrophages. 2C10 treatment also increased plaque α-smooth muscle content, and Gal-2 may have a role in modulating the inflammatory status of smooth muscle cells. Remarkably, both treatments reduced serum cholesterol concentrations including reductions in very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein while triglyceride concentrations were unchanged. Conclusion Prolonged and frequent treatment with anti-Gal-2 nanobodies reduced plaque size, slowed plaque progression, and modified the phenotype of plaque macrophages toward an anti-inflammatory profile. These results hold promise for future macrophage modulating therapeutic interventions that promote arteriogenesis and reduce atherosclerosis.

Abstract Background Oral contraceptive pill (OCP) use in the general population is associated with a failure rate as low as 0.3% with perfect use but as high as 9% with typical use. Women with Crohn’s disease (CD) may have malabsorption in the setting of small bowel disease or resection, which could affect absorption of OCPs. Our aim was to determine the incidence of pregnancy in women with CD on OCPs. Methods This is a retrospective study assessing the incidence rate of OCP failure in females between 18 and 45 years of age seen at the Mayo Clinic with a diagnosis of CD and provided a prescription for OCPs, between 2016 and 2020. Failure was defined as clear documentation of becoming pregnant while using OCPs or having an active prescription of OCP at the time of conception. Results A total of 818 female patients with CD between 18 and 45 years of age with a prescription for an OCP were included in our study. Sixty-six patients (8%) conceived in this cohort. Of the 66 patients who became pregnant, 57 stopped the OCP before conceiving, 5 were excluded due to lack of data, and 4 women had active oral contraceptive prescriptions when they became pregnant (pregnancy rate of 0.5%). Conclusions In female patients with CD who are using OCPs for contraception, we found a low rate of pregnancy (0.5%) similar to the rate of pregnancy with perfect use of OCPs in the general population. OCPs are an effective method of birth control in women with CD.