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INTRODUCTION Atrial fibrillation (AFib) is a recognized complication in patients with chronic lymphocytic leukemia (CLL) treated with Bruton tyrosine kinase inhibitors (BTKis). Early detection and management of AFib are critical due to its association with increased morbidity and mortality. Traditional detection methods, such as intermittent EKGs and wearable devices, often capture only brief snapshots of cardiac activity, potentially missing episodes. Recent advances in artificial intelligence (AI) have enabled the development of algorithms that analyze electrocardiograms (EKGs) to predict AFib risk. These algorithms can potentially identify patients with undetected AFib and assess risk at a single point, reducing the need for continuous monitoring. This study evaluates the utility of an AI-enabled EKG algorithm in predicting AFib in patients with CLL treated with ibrutinib and acalabrutinib. METHODS Patients with CLL treated with ibrutinib and acalabrutinib were identified from a single-center database. Patients with CLL who received BTKi therapy at Mayo Clinic between 2015 and 2024 with available EKGs in the EMR were included. Patients were excluded if they received BTKi for non-CLL indications or if patients with CLL had documented AFib without accompanying EKGs in their medical records. An AI-enabled EKG algorithm developed by Attia et al. (Lancet, 2019) was used to estimate AFib probability (AFibAI). EKGs were categorized into pre-treatment, during treatment, and post-treatment phases. Mean values of all EKGs within each phase were used for analysis to reduce heterogeneity. Paired t-test was used for continuous variables and ROC analysis was used to evaluate diagnostic performance. A p-value of <0.05 was used for statistical analysis. RESULTS The analysis included 383 individual CLL patients (74% male, median age71; ace/ethnicity not available), of which 79 were treated with acalabrutinib and 304 with ibrutinib, with a total of 5844 EKGs analyzed. The AFibAI was significantly higher in EKGs with documented AFib compared to other EKGs, mostly normal sinus rhythm (0.5710 vs. 0.1857, p <0.001). Pre-treatment AFibAI was higher in patients who ultimately developed AFib after starting BTKi treatment compared to those who did not. Mean AFibAI at baseline was 0.2176 for those who developed AFib and 0.0986 for those who did not (p <0.001; difference between means: -0.1191 +/- 0.02005, 95% CI: 0.-0.1585 - 0.0796). Differences of baseline AFibAI were similar when stratified by BTKi. Trends in AFibAI scores indicated a significant increase during and after BTKi treatment in patients who developed AFib, with mean score of 0.2176 at baseline to 0.4064 post-treatment (p<0.001). In patients who did not develop Afib during BTKi therapy, there was minimal increase of AFibAI scores from 0.1041 at baseline to 0.1620 post-treatment (p = 0.0002). The ROC analysis showed an area under the curve of 0.7280 (SE = 0.03911, 95% CI: 0.6514 to 0.8047, p <0.001), indicating fair discriminatory ability. The sensitivity at the optimal threshold (0.1202) was 65.45% and the specificity was 74.59%, with a Youden's Index of 0.4004. To achieve a sensitivity of ≥90% for detecting patients who ultimately develop AFib, a threshold of 0.2368 was established (specificity of 41.82%). DISCUSSION Our study demonstrates the efficacy of an AI-enabled EKG algorithm in estimating atrial fibrillation risk among CLL patients treated with BTKis. We demonstrated that baseline AFibAI was notably higher in patients who ultimately developed AFib, suggesting that it could potentially identify patients at elevated risk before the onset of AFib. Early identification would allow for closer monitoring and timely intervention, potentially mitigating complications. Pending validation with an external cohort, the 90% sensitivity threshold could help identify the patients at highest risk, where other treatment options could be considered. The trend across different treatment phases revealed a significant increase in scores during treatment, indicating that AFibAI is responsive to changes induced by BTKi therapy and suggest its utility for patient monitoring. Practical questions remain about its impact on clinical decision-making and management. Future prospective studies should confirm the validity of identifying high-risk patients and its role in both treatment decisions and patient outcomes.

Introduction: Multiple myeloma (MM) with t(11;14)(q13;q32), resulting in CCND1;IGH rearrangement, remains the only subset amenable to targeted therapy with the BCL2 inhibitor, Venetoclax. Nevertheless, not all patients with this translocation respond to treatment and some progress early after initial response. The mechanisms behind this clinical heterogeneity are largely unknown. Methods: To investigate mechanisms of heterogeneity in response to Venetoclax, we interrogated 44 whole genome sequencing (WGS) and 24 whole exome sequencing data from a training cohort including 33 patients with t(11;14) MM treated with Venetoclax at the Mayo Clinic. In a validation cohort, we extracted single nucleotide variants (SNV) and indels from 17 MM patients with t(11;14) with available RNAseq data treated with Venetoclax at Emory University. Results: In the training cohort the median number of lines of therapy was 4 and Venetoclax drug regimens included combinations with dexamethasone, proteasome inhibitors, anti-CD38 agents, and immunomodulatory agents. After a median follow up of 30 months, the median progression free survival (PFS) was 9 months, and 13 patients (39%) achieved a complete remission (CR) to therapy, while 9 (27%) were refractory (i.e. no response or progressed within the first 60 days). For our driver discovery analysis, we integrated SNV, indels, copy number variants (CNV) and structural variants (SV). Deletion 17p (del17p) or TP53 mutation, MCL1 gain/amp, and hyper-APOBEC did not correlate with PFS in our cohort (p=0.59, p=0.71, and p=0.05, respectively). In contrast, mutations involving the MAPK pathway (NRAS, KRAS, BRAF, FGFR3) displayed the strongest association with short PFS, which was retained after adjusting for del17p/TP53 mutations, and 1q gain/amp (HR: 4.76, CI: 1.8-12.9, p=0.002). The association between suboptimal response and resistance to Venetoclax in MM patients with MAPK pathway mutations (n=7) was also observed in our validation cohort from Emory University (p=0.046). This is in line with what has been reported in functional studies in acute myeloid leukemia, where RAS pathway promotes MCL1 under the selective pressure of Venetoclax (Zhang et al. Signal Transduct Target Ther 2022). While MAPK mutations explained most cases of refractory patients (86%), the mechanisms through which initially responding patients subsequently progressed remain unclear. To investigate this, we interrogated 10 patients with pre- and post-treatment samples collected at disease progression (PD). We identified genomic events acquired/selected at PD of genes involved in the anti-apoptotic MCL1/BCL2 and MAPK pathways in 6/10 cases. One patient was refractory to Venetoclax and had double minutes involving BCL2, which caused multiple focal amplifications (>30 copies), likely reflecting extrachromosomal DNA. Another patient progressed with an acquired, focal deletion on BCL2L11. In two patients, the progressing clones harbored mutations in MAPK pathways (one BRAF and the other WNK2). Two patients who relapsed after sustained CR had major branching evolution where a previously undetectable focal deletion of PMAIP1 (NOXA) was seen at PD. Importantly, one of these deletions was a biallelic event. Venetoclax sensitivity assays conducted on PMAIP1 knockout in the MM t(11;14) cell line, KMS12PE, demonstrated significantly reduced cell death across all drug concentrations (p<0.05), validating the loss of NOXA as a mechanism of resistance to Venetoclax in MM. Finally, similarly with what was previously reported in chronic lymphocyte leukemia treated with Venetoclax (e.g., Herling et al Nat Comm 2018), CDKN2A/B monoallelic and biallelic focal deletions were selected post-Venetoclax, at PD in 4 patients while TP53 SNV/deletions were selected from subclonal to clonal in 2 patients at PD. Conclusion: In this study, we demonstrate that mutations involving the MAPK pathway identify a population of MM patients with t(11;14)(CCND1;IGH) who are unlikely to respond to Venetoclax. We also show that genomic events involving the MAPK and BCL2/MCL1 pathways are primarily responsible for disease progression after initial response. These findings highlight the critical role of comprehensive genomic profiling through WGS in identifying mechanisms of resistance to targeted therapies in MM, aiding patient selection for Venetoclax, and guiding the development of novel drug combinations.

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: Cancer therapy-induced cardiotoxicity (CTRCD) is one of the most significant adverse effects of oncologic treatment, responsible for considerable morbidity and mortality. Heart failure stands out due to its higher frequency and severity with the focus of most studies being left ventricular dysfunction and remodeling. The right ventricle (RV) may also be damaged by CTRCD, however the effects on RV function have not been elucidated. Research Question: What are the echocardiographic changes in RV due chemotherapy treatment? Objective: To conduct a systematic review and meta-analysis evaluating the RV echocardiographic parameters in patients undergoing chemotherapy treatment. Methods: Pubmed, Embase and Cochrane were systematically searched for studies that assessed RV echocardiographic changes in patients due to chemotherapy treatment. Statistical analysis was performed using the R statistical environment, with a summary estimate using Mean Differences (MD), adopting a random-effects model to account for variability among studies and a two-tailed significance level of 5%. A correlation coefficient of 0.5 was assumed for the paired measurements. Heterogeneity was assessed using the I2 statistic. Results: We included 641 patients from 11 studies, 75.5% of whom were women and with a mean age of 50.2±6.1 years. RV function was significantly lower after cancer treatment, with reduction in the fractional area change (MD -3.53%; CI -5.25, -1.41; p<0.0011 - Figure 1A), RV global longitudinal strain (MD 2.27%; CI 1.24, 3.29; p<0.0011 - Figure 1B) and in RV free wall strain (MD 3.22%; CI 1.76, 4.67; p<0.0001 - figure 1C). Additionally, the pulmonary artery systolic pressure was significantly higher (MD 1.36mmHg; CI 0.32, 2.4; p=0.01 - Figure 1D) and the tricuspid annular plane systolic excursion was significantly reduced (MD -1.98mm; CI -3.27, -0.68; p=0.0027 - Figure 1E) after chemotherapy. Conclusion: RV dysfunction is common in CTRCD and its echocardiographic quantification should be included in clinical practice follow-up during cancer treatment. Further research is needed to elucidate the underlying factors contributing to RV dysfunction in CTRCD and to develop methods for its early detection.

Introduction: Portopulmonary hypertension (POPH) and associated pulmonary vascular resistance (PVR) elevation is seen in the context of underlying portal hypertension and liver disease. In the systemic circulation, liver cirrhosis can cause inappropriate splanchnic and systemic vasodilation with decreased systemic vascular resistance (SVR). Midodrine is used to maintain blood pressure in the setting of low SVR. Pulmonary vasodilators have systemic vasodilatory effects; the implications of combined midodrine and pulmonary vasodilator use in POPH are unanswered questions. Hypothesis: We hypothesized that SVR would decrease over time in patients with POPH started on pulmonary vasodilators, and that use of midodrine (as a surrogate for depressed SVR), may be associated with increased risk of mortality in patients with POPH starting pulmonary vasodilator therapy. Methods: Patients from the 3 Mayo Clinic sites (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) diagnosed with POPH from 1988-2020 were included in the database. Patients met hemodynamic criteria for POPH via right heart catheterization (RHC). Hemodynamics were obtained from echocardiography and RHC at initial and subsequent visits. The hazard ratio for risk of death was estimated using Cox proportional hazards method. SVR was calculated using mean arterial pressure and cardiac output. Results: Analysis included 147 POPH patients, 34 (23%) on midodrine and 113 (77%) not requiring midodrine. There were 116 patients with longitudinal SVR data. The mean initial SVR was 1224 Dyne sec cm-5 and decreased 251 Dyne sec cm-5 [95% CI -337 to -165 251 Dyne sec cm-5, p<0.0001] with no difference between midodrine groups (p=0.57). Patients in the midodrine POPH group had an increased risk of mortality compared to those without midodrine use (HR 1.51, 95% CI: 1.02-2.21, p=0.0371). Conclusions: Patients with POPH starting pulmonary vasodilator have a reduction in SVR related to vasodilator therapy. Midodrine use with pulmonary vasodilator therapy is associated with increased mortality in the POPH population. Further study of the safety of combined midodrine and pulmonary vasodilator use in POPH is needed along with exploration of more selective pulmonary vasodilators.

Positive remodeling (PR) is an atherosclerotic plaque feature defined as an increase in arterial caliber at the level of an atheroma, in response to increasing plaque burden. The mechanisms that lead to its formation are incompletely understood, but its role in coronary atherosclerosis has major clinical implications. Indeed, plaques with PR have elevated risk of provoking acute cardiac events. Hence, PR figures among the high-risk plaque features that cardiac imaging studies should report. This review aims to provide an overview of the current literature on coronary PR. It outlines the pathophysiology of PR, the different techniques used to assess its presence, and the imaging findings associated to PR, on both noninvasive and invasive studies. This review also summarizes clinical observations, trials, and studies, focused on the impact of PR on clinical outcome.

ObjectivesFetal growth restriction (FGR) is commonly associated with placental dysfunction, increasing perinatal morbidity and mortality. Visualizing placental vessels in utero would be advantageous for identifying functional FGR cause and determining proper management strategies. We aimed to utilize high‐sensitivity ultrasound microvessel imaging (HUMI) for quantifying placental vessel density (VD) in pregnancies diagnosed with FGR.MethodsThis pilot case–control study enrolled subjects in the third trimester with a diagnosis of FGR (n = 40) and gestational age‐matched controls with normal fetal growth (n = 20) at a 2:1 ratio, respectively. The Verasonics Vantage ultrasound system was used to perform HUMI on each participant at one timepoint. Scanning involved randomized singular value decomposition‐based clutter filtering to identify the villous tree, followed by step‐by‐step scanning to acquire 3‐dimensional‐like data. Mean VD was calculated from three ultrasound measurements per subject. Additional clinical and pathology data were also collected and compared.ResultsSixteen participants were utilized to establish the scanning protocol and 2 met exclusion criteria at delivery. Thus, VD was successfully measured on 42 pregnancies scanned at 35 weeks 5 days on average. In FGR (n = 24), placental VD was significantly reduced compared to controls (P < .01). VD measures were as good at predicting FGR as systolic/diastolic (S/D) ratios (area under the curve 0.86 versus 0.80). In a smaller cohort, VD in placentas with a diagnosis of inflammatory villitis (n = 10) by histology showed an increase in VD compared to those without inflammation (P = .01). Low VD was correlated with increased S/D ratios (P = .03).ConclusionsHUMI is useful for identifying altered placental vascularization in utero for FGR. VD may be a valuable indicator for placental health and could lead to improved risk stratification methods considering underlying biology.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis, but data are limited on younger, low-risk patients. This analysis compares outcomes in low-surgical-risk patients aged <75 years receiving TAVR versus surgery. METHODS: The Evolut Low Risk Trial randomized 1414 low-risk patients to treatment with a supra-annular, self-expanding TAVR or surgery. We compared rates of all-cause mortality or disabling stroke, associated clinical outcomes, and bioprosthetic valve performance at 3 years between TAVR and surgery patients aged <75 years. RESULTS: In patients <75 years, 352 were randomized to TAVR and 351 to surgery. Mean age was 69.1±4.0 years (minimum 51 and maximum 74); Society of Thoracic Surgeons Predicted Risk of Mortality was 1.7±0.6%. At 3 years, all-cause mortality or disabling stroke for TAVR was 5.7% and 8.0% for surgery ( P =0.241). Although there was no difference between TAVR and surgery in all-cause mortality, the incidence of disabling stroke was lower with TAVR (0.6%) than surgery (2.9%; P =0.019), while surgery was associated with a lower incidence of pacemaker implantation (7.1%) compared with TAVR (21.0%; P <0.001). Valve reintervention rates (TAVR 1.5%, surgery 1.5%, P =0.962) were low in both groups. Valve performance was significantly better with TAVR than surgery with lower mean aortic gradients ( P <0.001) and lower rates of severe prosthesis-patient mismatch ( P <0.001). Rates of valve thrombosis and endocarditis were similar between groups. There were no significant differences in rates of residual ≥moderate paravalvular regurgitation. CONCLUSIONS: Low-risk patients <75 years treated with supra-annular, self-expanding TAVR had comparable 3-year all-cause mortality and lower disabling stroke compared with patients treated with surgery. There was significantly better valve performance in patients treated with TAVR. REGISTRATION: URL: https://clinicaltrials.gov ; Unique identifier: NCT02701283.