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Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

Background: Mitral valve prolapse (MVP) is a common valvular abnormality. Observational studies demonstrate an association between MVP and increased risk of sudden cardiac death from ventricular arrhythmias, coined arrhythmogenic MVP. A genetic component has been postulated but remains under-investigated. Hypothesis: Predicted deleterious variants in Mendelian cardiomyopathy and arrhythmia genes are more frequent in arrhythmogenic MVP (aMVP) compared to non-arrhythmogenic MVP. Aims: To comprehensively phenotype and genotype a single-center aMVP cohort and compare to non-aMVP from two large population-based cohorts and investigate their clinical outcomes. Methods: The aMVP cohort included 46 prospectively enrolled patients from a regional referral center for inherited cardiovascular disease and had undergone multi-modality imaging and clinical gene panel testing. The non-aMVP comparator cohorts included 453 participants from the UK Biobank (UKBB), a prospective cohort of 500,000 UK residents, and 1,418 participants from the National Institutes of Health (NIH) All of Us (AoU), a prospective cohort of 450,000 USA participants. Gene variants were annotated in ANNOVAR. Participants with and without pathogenic/likely pathogenic (P/LP) variants reported on ClinVar with ≥2-star level of evidence were considered genotype positive (G+) and negative (G-) respectively. Results: The demographics for aMVP (age 61.2 ± 12.8 years, 56.5% female) and non-aMVP (UKBB: age 59.8 ± 7.3 years, 50.7% female and AoU: age 65.3 ± 13.4 years, 76.2% female) were comparable. G+ participants were more prevalent in the aMVP cohort 10/46 (21.7%) versus non-aMVP in the UKBB 8/453 (1.8%) and in the AoU 21/1418 (1.5%); p<0.001. The most frequently implicated gene in aMVP was TTN . Of 46 in aMVP cohort, 33 (71%) underwent CMR. G+ participants had a higher frequency of late gadolinium enhancement [6/6 (100%) vs. 14/27 (51.8%), p<0.001] and wall motion abnormalities [3/6 (50%) vs. 1/27 (3.7%), p<0.001] compared to G- participants. The aMVP cohort had significantly more implantable cardioverter defibrillator (ICD) implants compared to non-aMVP cohort [5/46 (10.9%) vs. 1/453 in UKBB (0.2%), p<0.001]. G+ aMVP cohort showed a trend for developing heart failure and ICD implants compared to G- aMVP . Conclusion: P/LP variants in cardiomyopathy and arrhythmia genes are more prevalent in aMVP participants compared to non-aMVP participants. This could be a hitherto unrecognized effect modifier predicting aMVP .

Introduction: Anthracyclines (AC), a class of chemotherapeutic drugs, are used to treat various cancers, including breast cancer (BC). However, AC cause dose-dependent cardiac toxicity. Practice guidelines list pre-existing cardiomyopathy as a risk factor for cancer therapy-related cardiac dysfunction (CTRCD), but there is a lack of data on cardiotoxicity risk in patients with left ventricular (LV) hypertrabeculation without LV hypertrophy/dilation. We present a patient with LV hypertrabeculation who developed LV dysfunction after AC chemotherapy for BC. Description of Case: A 55-year-old woman diagnosed with multicentric invasive ductal carcinoma (IDC) of the right breast, stage IIA (cT3 cN1 cM0), grade 2, ER+/PR+/HER2-, was treated with neoadjuvant Paclitaxel for 3 months. Before AC-based chemotherapy, stress cardiac MRI due to residual post-COVID-19 dyspnea showed LV hypertrabeculation with a non-compacted/compacted ratio of 2.3, LVEF 56%, and no delayed enhancement. Transthoracic echocardiography (TTE) reported an LVEF of 52% with GLS of -17%. The patient's electrocardiogram (ECG) showed normal sinus rhythm, and NT-pro BNP levels were <20 pg/mL. Genetic testing identified a rare variant in MYH7-encoded myosin heavy chain 7 (p.Arg941Leu-MYH7). She had no cardiovascular (CV) risk factors or family history of CV disease. She then underwent 4 cycles of Doxorubicin (cumulative dose 232.2 mg/m2) and Cyclophosphamide, followed by bilateral mastectomy and adjuvant radiotherapy (5000 cGy in 25 fractions). One year after chemotherapy, follow-up TTE showed LVEF decreased to 45% with GLS of -17%. The patient’s ECG remained normal, and NT-pro BNP levels were <36 pg/mL. Despite an LVEF decline, not all criteria for CTRCD were met, suggesting a gene-environment interplay between her chemotherapy and pre-existing MYH7-mediated non-dilated LV cardiomyopathy (NDLVC) with hypertrabeculation. The patient has remained without symptoms of heart failure and is currently taking Letrozole 2.5 mg daily. Discussion: This case offers a unique perspective on a BC patient treated with AC chemotherapy, who has a possible MYH7-mediated NDLVC with hypertrabeculation, and who experienced an LVEF decline of indeterminate significance. While the association of her possible NDLVC with hypertrabeculation is uncertain, the safety of AC in patients with isolated hypertrabeculation or NDLVC with hypertrabeculation, as introduced by the 2023 ESC cardiomyopathy guidelines, remains to be defined.

Introduction: Peripheral arterial disease (PAD) is caused by a lack of blood flow to the musculature relative to its metabolism which results in pain. PAD impacts up to 20% of patients around the world. PAD involves macrovascular and microvascular dysfunction. Near-infrared spectroscopy (NIRS) measures muscle oxygenation levels and assesses microvascular function. The standard of care for diagnosing PAD is the ankle-brachial index (ABI), which assesses macrovascular disease, and the 6-minute walk test (6MWT), which measures gait speed and claudication. NIRS has the potential to monitor progression of PAD. Hypothesis: NIRS measurement of muscle oxygenation, during a standard test of vascular occlusion and post-occlusive hyperemia, the vascular occlusion test (VOT), is predictive of PAD severity as determined by ABI and 6MWT. Methods: We studied 24 patients diagnosed with PAD. The mean age of the patients was 71.3 years, including 54% (n=13) males and 46% (n=11) females. The VOT consisted of rest, occlusion, and reperfusion phases each lasting 5 min (15 min total). Muscle oxygen saturation levels were recorded at 2 hertz. For every patient, 6 features were extracted from the VOT data using computational methods. The VOT features from 15 patients were used to train function-fitting neural network models to predict ABI and 6MWT Continuous Distance. The models were then used to predict ABI and 6MWT Continuous Distance from the VOT features of 9 test patients not used in the training, Results: For patients in the test set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 14%±13% and 15%±17%, respectively (Figure 1). For patients in the training set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 0±0% and 12%±11%, respectively (Figure 1). Conclusion: The VOT has the potential to predict the ABI and 6MWT Continuous Distance of patients diagnosed with PAD, suggesting that the VOT can be automated and used to monitor the severity of PAD. With more data from both healthy patients and PAD patients, and improvement of the model, we anticipate that the VOT will complement ABI and 6MWT in the diagnosis and monitoring of PAD.

Introduction/Background: Patients admitted with sepsis are at risk of developing septic cardiomyopathy (SCM), which may elevate their risk of short-term mortality. However, the effect of SCM on long-term outcomes after sepsis is poorly understood. This study explores whether patients with sepsis and SCM have worse long-term outcomes compared to those without SCM. Research Questions/Hypothesis: What are the long-term major adverse cardiovascular events, including death, stroke, and myocardial infarction (MACE) 36 months after ICU discharge for septic patients with abnormal global left ventricular strain (LV GLS)? Methods: We conducted a retrospective study of 396 sepsis patients from August 2018 to September 2022, approved by the Mayo Clinic IRB. Patient demographics, comorbidities, echo parameters, and outcomes were collected. Due to the expected non-linear relation between LV GLS and Hazard Ratio (HR) of MACE we employed Cox regression analysis with Restricted Cubic Splines. Secondly, we divided the population into 2 groups, patients with and without normal LV GLS (between -23 and -16). The effect of non-normal LV GLS on MACE was evaluated using Cox regression weight by inverse probability weighting (IPWT) analysis after propensity score assessment, adjusting for diabetes, hypertension, BMI, history of stroke or myocardial infarction, chronic kidney disease, age, and sex. Results: Demographic variables did not differ significantly based on normal versus abnormal LV GLS. In the restricted cox regression with cubic spline models, we observed that patients with normal values had HR lower than one compared with patients without normal values (Figure 1). Secondly, we found that the HR of MACE in patients with normal LV GLS was significantly lower in the crude analysis (HR 0.66 [CI 95% 0.5, 0.86]; p<0.01) and in the analysis adjusted by IPWT (HR 0.7 [CI 95% 0.53, 0.92]; p=0.01). Conclusion: Sepsis patients with abnormal global left ventricular strain (LV GLS) have a higher risk of major adverse cardiovascular events (MACE) within 36 months post-ICU discharge compared to those with normal strain. LV GLS values outside the range of -23 to -16 are associated with increased risk. Monitoring LV GLS in sepsis patients is important for identifying those at elevated risk for long-term cardiovascular complications.

Introduction: The incidence and risk factors for atrial arrhythmia (AA) [atrial fibrillation (AF) and atrial flutter (AFL)] in adults with systemic right ventricle (SRV), specifically congenitally corrected-TGA (cc-TGA) and D-TGA palliated with atrial switch procedures, is not well understood. This study aims to better define these risks. Methods: Adults with SRV presenting to the Mayo Clinic between 1971 and 2022 were identified. Clinical characteristics, ECG and echocardiographic parameters were recorded at first evaluation. Sustained AA (> 30s) incidence at follow-up was documented using ECG. Cox regression analysis identified associations of incident AA. Results: Among 447 patients with SRV (mean age 34.7±14.8, 55.9% male, cc-TGA n=247; D-TGA post-atrial baffle n=200), AA was documented in 231 (51.6%) at a mean age of 37.5±18.8y. Isolated AF was observed in 88 (38.1%), isolated AFL in 71 (30.7%), and both AF and AFL in 72 (31.2%) patients. Univariate analysis showed significant predictors of AA as: age (HR:1.03, p<0.001), male sex (HR:1.49, p=0.026), NYHA class≥2 (HR:1.98, p<0.001), ventricular pacing (HR:1.64, p=0.019), QRS duration (HR:1.008, p<0.001), SRV enlargement (HR:1.73, p=0.01), SRV ejection fraction (HR:0.979,p=0.012), left atrial enlargement (HR:1.947, p=0.006), hypertension (HR:1.57, p=0.047), CKD (HR:0.991, p=0.021), and obesity (HR:1.66, p=0.023). In multivariable analysis, age (HR:1.032, p<0.001) and QRS duration (HR:1.007, p=0.013) were significant predictors of AA. Kaplan Meier analysis of time from first evaluation to incidence of AA is shown in the figure. AA was associated with heart failure in 56 (26.7%) patients. During 11.2±10.5 years of follow-up, mortality occurred in 50 (21.6%) with AA and 19 (8.8%) without AA. Conclusion: Atrial arrhythmia occurred in more than half of patients with SRV, predominantly in the third decade of life. Significant associations of AA included advancing age, longer QRS duration, enlargement of pulmonary venous atrium, reduced SRV function, hypertension and obesity. AA was associated with heart failure in one-fourth of patients and higher mortality. Close monitoring and early intervention in patients with risk factors may help mitigate the development of AA.

Introduction: Peripheral artery disease (PAD), an atherosclerotic disease of the peripheral arteries, also results in microvascular dysfunction. PAD patients are recommended to undergo supervised walking and medical management; however, compliance with supervised walking programs is limited due to inconvenience and pain, necessitating alternative non-pharmacological interventions. We have shown that daily muscle stretching improved microvascular function in aged rats. This prompted us to study the effect of daily muscle stretching on microvascular function of the calf muscles in PAD patients. Methods: A randomized, single-blinded study was conducted on 24 PAD patients. Patients were assigned to either stretching or placebo stretching using a dorsiflexion splint (Image 1) for 30 min/day, 5 days/wk for 4 wks. Calf muscle oxygen saturation (smO 2 ) was recorded using near-infrared spectroscopy during the six-minute walking test (6MWT) before (Visit 1) and after (Visit 2) stretching or placebo stretching. The percentage decrease in smO 2 (from baseline) at minute 1 (Δ1) and minute 2 (Δ2) of the 6MWT was determined. Two-way ANOVA was used to compare Δ1 and Δ2 between the stretching and placebo stretching groups. Results: The mean age of the patients was 74.1±11.4 yrs with 52% (13/23) males. There was no significant difference in the changes in smO 2 during the 6MWT at either minute 1 (Δ1: 44.1±7.3% vs 27.1±7.0%, p=0.12) or minute 2 (Δ2: 78.7±8.2% vs 58.1±7.9%, p=0.08) between the stretching group and placebo stretching group at Visit 1. In contrast, at Visit 2, there was a significantly greater change in smO 2 at minute 2 (D2: 83.1±8.2% vs 51.3±7.9%, p=0.008) in the stretching group compared to the placebo stretching group with a trend towards a statistically greater change in smO 2 at minute 1 (Δ1: 39.0±7.3% vs 20.4±7.0%, p=0.06) (Image 2). Conclusion: Daily stretching of the calf muscles for 4 weeks is associated with increased oxygen extraction by the calf muscles during walking.

Background: Pulmonary vascular resistance (PVR) is commonly considered to reflect opposition to lung blood flow caused by the arteries (PVRa), but downstream venous resistance (PVRv) may also contribute to pulmonary hypertension (PH) associated with left heart diseases (PH-LHD). In patients referred for right heart catheterization, we investigated PVR distribution and its pathophysiologic implications in PH-LHD and other forms of PH. Methods: Patients with PH-LHD (n=292), pulmonary veno-occlusive disease (PVOD, n=10), chronic thromboembolic PH (CTEPH, n=36) and controls without PH (Ctrl, n=28) were included. Pulmonary capillary pressure (Pc) was calculated using the pulmonary artery occlusion technique. PVR was partitioned into PVRa ((mPAP-Pc)/CO) and PVRv ((Pc-PAWP)/CO) with each expressed as % of PVR. PH-LHD was divided into isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). Further, PH-LHD was categorized as heart failure with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction or left valvular heart disease (L-VHD). In subsets, functional tests (n=71-81) and histological pulmonary venous (PV) remodeling (autopsy, n=15) were performed to investigate correlations with PVR distribution. Results: PVR distribution showed an arterial predominance in Ctrl and CTEPH, and increasing venous contribution in PH-LHD (both IpcPH and CpcPH) and PVOD (Figure A-F). In PH-LHD, patients with HFpEF had proportionately greater venous contribution to PVR than HFrEF and L-VHD (Figure G-I), though not to the extent observed in PVOD. In subsets, PVRv was more strongly correlated with E/e’, extravascular lung water estimated by sonographic B-lines, arterial PO 2 , pulmonary dead space fraction (VD/VT), DLCO, and, among the autopsy series, PV intimal thickness as compared to PVRa (Figure J-O). Conclusions: Pulmonary venous contributions to PVR are amplified in patients with PH-LHD, which is correlated with greater lung congestion, ventilatory and gas exchange abnormalities, and histological venous remodeling. Further study is required to determine the molecular mechanism and novel therapeutics of pulmonary venous disease in PH-LHD.

Background: Dysfunction of systemic vascular endothelial cells (ECs) is common in heart failure with preserved ejection fraction (HFpEF). We sought to determine if organ-specific EC translational heterogeneity is present in HFpEF. Using a transgenic mouse model (RiboTag EC ), we analyzed the translatome (the mRNAs bound with ribosomes) of organ-specific ECs in a mouse HFpEF model induced by hypertensive/metabolic stresses. Methods: Six-month-old male RiboTag EC ( Cdh5 CreERT2+ / Rpl22 HA/+ ) mice, expressing a hemagglutinin tag in EC ribosomal protein Rpl22, were fed a high-fat diet and L-NAME water (N=4) or a normal diet and water (N=5) for 7 weeks. Organs were collected for Translating Ribosome Affinity Purification, RNA isolation, and RNA-seq. RNA-seq data were visualized using uniform manifold approximation and projection (UMAP). Differentially expressed genes (DEGs; absolute fold change ≥ 2 and false discovery rate (FDR) adjusted p-value ≤ 0.05). Pathway enrichment analyses were conducted (Ingenuity Pathways Analysis (IPA)). Results: In UMAP, the EC translatome clustered by organ (heart, lung, skeletal muscle, and liver) highlighting organ-specific EC heterogeneity and by disease (HFpEF) status with cardiac ECs showing the most dramatic changes with HFpEF (Fig A). Cardiac ECs in HFpEF (vs Control) had 283 downregulated and 23 upregulated DEG (Fig B) out of 14,923 genes identified. There were significant differences in 142 canonical pathways (16 upregulated, 126 downregulated), including LXR/RXR activation, DHCR 24 signaling, regulation of insulin-like growth factors, eNOS signaling, acute phrase response (all down regulated) and IL-1b-mediated inhibition of RXR and unfolded protein response (both up regulated) (Fig C). Conclusion: HFpEF induction caused extensive translational changes in EC but particularly cardiac ECs. In cardiac ECs, metabolism, anti-inflammatory, vasodilation, tissue repair, and angiogenesis pathways were inhibited, while pro-inflammatory response, insulin resistance, and proteostasis pathways were activated.

Background: Cardiopulmonary Exercise Testing (CPET) analyzes physiologic information with gas exchange during exercise. Peak oxygen volume consumption (absolute peak VO2 and percent predicted peak VO2), minute ventilation divided by carbon dioxide volume (VE/VCO2 slope) and heart rate reduction after 1 minute of recovery (heart rate recovery, HRR) all have well-established prognostic cardiovascular implications. Aim: Given the wider use of echocardiography, we aimed to see if important CPET data could be determined from resting transthoracic echocardiography (TTE). Methods: In this retrospective study, cardiology patients above 18 years who underwent both resting TTE and a max-effort CPET within 3 months of each other (2017-2022) were included. Patients with a history of coronary artery bypass grafting, valve surgery, pacemakers, congenital heart disease, severe valve dysfunction and pulmonary hypertension were excluded before analysis. Univariate analysis with Spearman correlations was used to assess the relationship between 4 CPET measurements {absolute peak VO2 per kg, percent predicted peak VO2/kg (adjusted for age, sex and body surface area), HRR, and VE/VCO2}; and 22 quantitative TTE parameters. Bonferroni correction was applied within each set of correlations, with significance set at p-values <0.025. Multivariate linear regression models were built for all the related TTE measurements to assess relationship with the 4 CPET parameters, adjusting for age and sex. Results: Table 1 shows, out of 1909 patients analyzed, our regression model is strongest for absolute peak VO2/kg (R-squared=0.57), with 3 significantly associated TTE parameters. For percent-predicted peak VO2 per kg, 4 TTE variables were significantly associated. For heart rate recovery, only LV stroke-volume index was correlated. No TTE parameters were associated with VE/VCO2. Conclusion: Notably, echocardiographic stroke volume and tricuspid valve regurgitation peak velocity exhibited a strong correlation with absolute peak VO2/kg and percent predicted peak VO2/kg. LV stroke volume index was correlated with heart rate recovery. VE/VCO2 was not associated with any resting echocardiographic parameters, suggesting this parameter is truly exercise-dependent.