Disproportionately High Aortic Valve Calcium Scores in Atrial Fibrillation: Implications for Transcatheter Aortic Valve Replacement.

AIMS: Doppler mean gradient (MG) can underestimate aortic stenosis (AS) severity in patients with atrial fibrillation (AF) compared to patients in sinus rhythm (SR), potentially delaying intervention in AF. This study compared outcomes in patients with AF and SR following transcatheter aortic valve replacement (TAVR) and investigated delay in TAVR based on computed tomography aortic valve calcium score (AVCS). METHODS AND RESULTS: Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. Baseline characteristics and overall survival were compared between those in SR and AF. There were 820 patients (mean age 81 years; 41.6% female) included. AF was present in 356 patients. Patients in AF were older (82.2 vs. 80.5, p = 0.003), had lower MG compared to SR patients (42.0 vs. 44.9, p = 0.002) with similar indexed aortic valve area (0.4 vs. 0.4, p = 0.17). Median AVCS was higher in AF (males: AF 2850.0 vs. SR 2561.0, p = 0.044; females: AF 1942.0 vs. SR 1610.5, p = 0.025). Projected AVCS assuming same age of diagnosis was similar between AF and SR. Median survival post-TAVR was worse in AF compared to SR (3.2 vs 5.4 years, log rank p < 0.001). AF, lower MG, higher RVSP, dialysis, diabetes, and significant TR were associated with higher mortality (p < 0.05 for all). CONCLUSION: Older age and higher AVCS in patients with AF compared to SR suggests that AS was both underestimated and more advanced at TAVR referral.

Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence. METHODS: We conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively. RESULTS: Of 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant. CONCLUSION: There is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.

Analysis of Worsening Heart Failure Events in an Integrated Health Care System.

BACKGROUND: There is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. OBJECTIVES: The purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. METHODS: We studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. RESULTS: We identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. CONCLUSIONS: ED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

A Natural Language Processing-Based Approach for Identifying Hospitalizations for Worsening Heart Failure Within an Integrated Health Care Delivery System.

Importance: The current understanding of epidemiological mechanisms and temporal trends in hospitalizations for worsening heart failure (WHF) is based on claims and national reporting databases. However, these data sources are inherently limited by the accuracy and completeness of diagnostic coding and/or voluntary reporting. Objective: To assess the overall burden of and temporal trends in the rate of hospitalizations for WHF. Design, Setting, and Participants: This cohort study, performed from January 1, 2010, to December 31, 2019, used electronic health record (EHR) data from a large integrated health care delivery system. Exposures: Calendar year trends. Main Outcomes and Measures: Hospitalizations for WHF (ie, excluding observation stays) were defined as 1 symptom or more, 2 objective findings or more including 1 sign or more, and 2 doses or more of intravenous loop diuretics and/or new hemodialysis or continuous kidney replacement therapy. Symptoms and signs were identified using natural language processing (NLP) algorithms applied to EHR data. Results: The study population was composed of 118 002 eligible patients experiencing 287 992 unique hospitalizations (mean [SD] age, 75.6 [13.1] years; 147 203 [51.1%] male; 1655 [0.6%] American Indian or Alaska Native, 28 451 [9.9%] Asian or Pacific Islander, 34 903 [12.1%] Black, 23 452 [8.1%] multiracial, 175 840 [61.1%] White, and 23 691 [8.2%] unknown), including 65 357 with a principal discharge diagnosis and 222 635 with a secondary discharge diagnosis of HF. The study population included 59 868 patients (20.8%) with HF with a reduced ejection fraction (HFrEF) (<40%), 33 361 (11.6%) with HF with a midrange EF (HFmrEF) (40%-49%), 142 347 (49.4%) with HF with a preserved EF (HFpEF) (≥50%), and 52 416 (18.2%) with unknown EF. A total of 58 042 admissions (88.8%) with a primary discharge diagnosis of HF and 62 764 admissions (28.2%) with a secondary discharge diagnosis of HF met the prespecified diagnostic criteria for WHF. Overall, hospitalizations for WHF identified on NLP-based algorithms increased from 5.2 to 7.6 per 100 hospitalizations per year during the study period. Subgroup analyses found an increase in hospitalizations for WHF based on NLP from 1.5 to 1.9 per 100 hospitalizations for HFrEF, from 0.6 to 1.0 per 100 hospitalizations for HFmrEF, and from 2.6 to 3.9 per 100 hospitalizations for HFpEF. Conclusions and Relevance: The findings of this cohort study suggest that the burden of hospitalizations for WHF may be more than double that previously estimated using only principal discharge diagnosis. There has been a gradual increase in the rate of hospitalizations for WHF with a more noticeable increase observed for HFpEF.

Risks and benefits of concurrent treatment with antiplatelet and anticoagulation therapy in post-op bioprosthetic aortic valve replacement patients.

BACKGROUND AND AIM: Among patients receiving surgical bioprosthetic aortic valve replacement (bAVR), there is an elevated risk of thromboembolic events postoperatively. However, the risks and benefits of varying anticoagulation strategies remain controversial. The aim of this study is to compare the risks and benefits of aspirin monotherapy to aspirin plus warfarin ("concurrent therapy") in patients receiving bAVR. METHODS: A retrospective cohort study was conducted using patients' data from Kaiser Permanente Northern California, including those who underwent bAVR with or without coronary artery bypass grafting between 2009 and 2018. Patients were identified as having been discharged with aspirin only or concurrent therapy. The outcomes were mortality, thromboembolic events, and clinically relevant bleeding during a 6-month follow-up. The event rates were compared using the Kaplan-Meier method. Multivariable survival analysis, incorporating propensity scores, was used to estimate adjusted hazard ratios (aHRs) for each outcome. RESULTS: The cohort consisted of 3047 patients. Approximately 58% of patients received aspirin only and 42% received concurrent therapy. Patients who received concurrent therapy were more likely to be older, have hypertension, previous stroke, and longer hospital stays. After adjustment using multivariable analysis, concurrent therapy was associated with a higher risk of clinically relevant bleeding (aHR, 2.33; 95% confidence interval, 1.67-3.25). There was no significant difference in the risk of thromboembolic events or mortality between the two groups. CONCLUSION: Patients who underwent bAVR and were discharged on concurrent therapy compared to aspirin only had a significantly increased risk of bleeding without a significant difference in thromboembolic events.

A Novel In-hospital Congestion Score to Risk Stratify Patients Admitted for Worsening Heart Failure (from ASCEND-HF).

Patients hospitalized for heart failure (HF) remain at high risk for early readmission. A post hoc analysis was performed of the biomarker substudy of the ASCEND-HF trial. An in-hospital congestion score was derived using orthopnea, pedal edema, and NT-proBNP levels. Its added prognostic value beyond traditional risk factors was assessed by determining the net reclassification index (NRI). Study participants (n = 884) had a median age (years) of 67 (55-77), 68% were male, and the median (25th-75th) ejection fraction (%) was 26 (20-40). After adjustment, increasing congestion score was associated with 30-day all-cause mortality or HF hospitalization (odds ratio = 1.51, 95% confidence interval [CI] 1.28-1.77, p < 0.001) and 180-day all-cause mortality (hazard ratio = 1.48, 95% CI 1.28-1.72, p < 0.001). However, adding the congestion score to the multivariable model did not significantly impact the NRI. A higher in-hospital congestion score portended a poor short-term prognosis but did not significantly reclassify risk.

Possible Precipitation of Acute Coronary Syndrome with Immune Checkpoint Blockade: A Case Report.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have led to improved survival in patients with a number of different tumor types. The ICI agent nivolumab induces anti-tumor immune responses by inhibiting the programmed cell death 1 protein, but side effects include cardiac immune-related adverse events (irAE) such as myocarditis.¹ The association of nivolumab with atherosclerotic disease has been rarely reported. CASE PRESENTATION: A 62-year-old man with metastatic melanoma and recent myocardial infarction (MI) presented with recurrent MI after having undergone several cycles of nivolumab therapy. Repeat cardiac catheterization revealed rapidly progressive in-stent restenosis and diffuse coronary artery disease (CAD) requiring bypass surgery and warranting cessation of nivolumab therapy. CONCLUSION: Nivolumab has been linked with dysregulation of immune responses including enhanced T cell activity, which is implicated in CAD. The timing of nivolumab therapy and presentation with non ST elevation myocardial infarction in this patient suggests a serious T cell-driven medication adverse effect. Therefore, close monitoring for atherosclerotic disease progression is warranted in patients on immunotherapy.

Incidence rates of cardiovascular outcomes in a community-based population of cancer patients.

BACKGROUND: There are limited data on the incidence of cardiovascular disease among cancer patients in the pre-tyrosine kinase inhibitor (TKI) era. Such data are important in order to contextualize the incidence of various cardiovascular outcomes among cancer patients enrolled in clinical trials of new agents and for postmarketing surveillance. METHODS: A retrospective cohort study was conducted using data from the Kaiser Permanente Northern California (KPNC) population of cancer patients. The inclusion criterion was a KPNC Cancer Registry diagnosis of any of several selected solid and hematologic tumors between 1997 and 2009 not treated with a TKI. Endpoints were identified using ICD-9 codes and included acute coronary syndrome, heart failure, stroke, cardiac arrest, hypertension, venous thromboembolism, all-cause mortality, and cardiovascular mortality. Event rates were calculated according to type of cancer and number of cardiovascular risk factors. RESULTS: The study included almost 165 000 individuals with a broad variety of tumor types. The parent cohort was 54% female and 35% were ≥70 years old. Cardiovascular risk factors such as diabetes mellitus (14% of patients with solid tumors, 15% of patients with liquid tumors), dyslipidemia (33%, 31%), hypertension (50%, 49%), and smoking (35%, 32%) were common. The most frequent adverse outcomes were incident hypertension (26.8-61.0 cases per 1000 person-years, depending on the type of cancer), heart failure (9.4-78.7), and acute coronary syndrome (2.6-48.1). These event rates are high compared to what has been reported in prior KPNC cohort studies of patients without cancer. The rates of acute coronary syndrome, heart failure, and ischemic stroke increased with increasing numbers of cardiovascular risk factors. CONCLUSIONS: In a population of patients with cancer not exposed to TKIs, cardiovascular risk factors and outcomes are very common, regardless of cancer type. These data can inform the evaluation of potential excess cardiovascular risks from new interventions.

Evolution of CpG island promoter function underlies changes in KChIP2 potassium channel subunit gene expression in mammalian heart.

Scaling of cardiac electrophysiology with body mass requires large changes in the ventricular action potential duration and heart rate in mammals. These changes in cellular electrophysiological function are produced by systematic and coordinated changes in the expression of multiple ion channel and transporter genes. Expression of one important potassium current, the transient outward current (I(to)), changes significantly during mammalian evolution. Changes in I(to) expression are determined, in part, by variation in the expression of an obligatory auxiliary subunit encoded by the KChIP2 gene. The KChIP2 gene is expressed in both cardiac myocytes and neurons and transcription in both cell types is initiated from the same CpG island promoter. Species-dependent variation of KChIP2 expression in heart is mediated by the evolution of the cis-regulatory function of this gene. Surprisingly, the major locus of evolutionary change for KChIP2 gene expression in heart lies within the CpG island core promoter. The results demonstrate that CpG island promoters are not simply permissive for gene expression but can also contribute to tissue-selective expression and, as such, can function as an important locus for the evolution of cis-regulatory function. More generally, evolution of the cis-regulatory function of voltage-gated ion channel genes appears to be an effective and efficient way to modify channel expression levels to optimize electrophysiological function.