Comparing outcomes after pulmonary vein isolation in patients with systolic and diastolic heart failure.

Background: The benefit of pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) is well established; its efficacy in patients with heart failure preserved ejection fraction (HFpEF) is less clear. Objective: The objective of the study was to compare AF and heart failure (HF) rehospitalizations after PVI in patients with HFpEF vs HFrEF. Methods: The IBM MarketScan Database was used to identify patients undergoing PVI for AF. Patients were categorized by HF status: absence of HF, presence of HFrEF, or presence of HFpEF. Primary outcomes were HF and arrhythmia hospitalizations after PVI. Results: A total of 32,524 patients were analyzed: 27,900 with no HF (86%), 2948 with HFrEF (9%), and 1676 with HFpEF (5%). Compared with those with no HF, both patients with HFrEF and HFpEF were more likely to be hospitalized for HF (hazard ratio [HR] 7.27; P < .01 for HFrEF and HR 9.46; P < .01 for HFpEF) and for AF (HR 1.17; P < .01 for HFrEF and HR 1.74; P < .01 for HFpEF) after PVI. In matched analysis, 23% of patients with HFrEF and 24% patients with HFpEF demonstrated a reduction in HF hospitalizations (P = .31) and approximately one-third demonstrated decreased arrhythmia rehospitalizations (P = .57) in the 6 months after PVI. Compared with those with HFrEF in longer-term follow-up (>1 year), patients with HFpEF were more likely to have HF (HR 1.30; P < .01) and arrhythmia (HR 1.19; P < .01) rehospitalizations. Conclusion: Reductions in HF and arrhythmia hospitalizations are observed early after PVI across all patients with HF, but patients with HFpEF demonstrate higher HF rehospitalization and arrhythmia recurrence in longer-term follow-up than do patients with HFrEF.

A Revised Definition of Left Bundle Branch Block Using Time to Notch in Lead I.

Importance: Current left bundle branch block (LBBB) criteria are based on animal experiments or mathematical models of cardiac tissue conduction and may misclassify patients. Improved criteria would impact referral decisions and device type for cardiac resynchronization therapy. Objective: To develop a simple new criterion for LBBB based on electrophysiological studies of human patients, and then to validate this criterion in an independent population. Design, Setting, and Participants: In this diagnostic study, the derivation cohort was from a single-center, prospective study of patients undergoing electrophysiological study from March 2016 through November 2019. The validation cohort was assembled by retrospectively reviewing medical records for patients from the same center who underwent transcatheter aortic valve replacement (TAVR) from October 2015 through May 2022. Exposures: Patients were classified as having LBBB or intraventricular conduction delay (IVCD) as assessed by intracardiac recording. Main Outcomes and Measures: Sensitivity and specificity of the electrocardiography (ECG) criteria assessed in patients with LBBB or IVCD. Results: A total of 75 patients (median [IQR] age, 63 [53-70.5] years; 21 [28.0%] female) with baseline LBBB on 12-lead ECG underwent intracardiac recording of the left ventricular septum: 48 demonstrated complete conduction block (CCB) and 27 demonstrated intact Purkinje activation (IPA). Analysis of surface ECGs revealed that late notches in the QRS complexes of lateral leads were associated with CCB (40 of 48 patients [83.3%] with CCB vs 13 of 27 patients [48.1%] with IPA had a notch or slur in lead I; P = .003). Receiver operating characteristic curves for all septal and lateral leads were constructed, and lead I displayed the best performance with a time to notch longer than 75 milliseconds. Used in conjunction with the criteria for LBBB from the American College of Cardiology/American Heart Association/Heart Rhythm Society, this criterion had a sensitivity of 71% (95% CI, 56%-83%) and specificity of 74% (95% CI, 54%-89%) in the derivation population, contrasting with a sensitivity of 96% (95% CI, 86%-99%) and specificity of 33% (95% CI, 17%-54%) for the Strauss criteria. In an independent validation cohort of 46 patients (median [IQR] age, 78.5 [70-84] years; 21 [45.7%] female) undergoing TAVR with interval development of new LBBB, the time-to-notch criterion demonstrated a sensitivity of 87% (95% CI, 74%-95%). In the subset of 10 patients with preprocedural IVCD, the criterion correctly distinguished IVCD from LBBB in all cases. Application of the Strauss criteria performed similarly in the validation cohort. Conclusions and Relevance: The findings suggest that time to notch longer than 75 milliseconds in lead I is a simple ECG criterion that, when used in conjunction with standard LBBB criteria, may improve specificity for identifying patients with LBBB from conduction block. This may help inform patient selection for cardiac resynchronization or conduction system pacing.

Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers.

STAT3 mutations, predominantly in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause rare cases of immunodeficiency, malignancy, and autoimmunity. The exact mechanisms by which these mutations abrogate or enhance STAT3 function are not completely understood. Here, we examined how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations within the DBD and SH2D affect monomer and homodimer protein stability as well as their effect on key STAT3 activation events, including recruitment to phosphotyrosine (pY) sites within peptide hormone receptors, tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding. The DBD LOF mutants showed reduced DNA binding when homodimerized, whereas the DBD GOF mutants showed increased DNA binding. DBD LOF and GOF mutants showed minimal changes in other STAT3 functions or in monomer or homodimer protein stability. However, SH2D LOF mutants demonstrated reduced conformational stability as either monomers or homodimers, leading to decreased pY-peptide recruitment, tyrosine phosphorylation, dimerization, nuclear localization, and DNA binding. In contrast, cancer-causing SH2D GOF mutants showed increased STAT3 homodimer stability, which increased their DNA binding. Of note, a small-molecule inhibitor of STAT3 that targets the tyrosine phosphopeptide-binding pocket within the STAT3 SH2D potently inhibited cell proliferation driven by STAT3 SH2D GOF mutants. These findings indicate that the stability of STAT3 protein monomer and homodimer is critical for the pathogenesis of diseases caused by SH2D LOF and GOF mutations and suggest that agents that modulate STAT3 monomer and/or homodimer protein stability may have therapeutic value in diseases caused by these mutations.

Population-Level Impact of the Guidelines Update on Patient Selection and Outcomes After Cardiac Resynchronization Therapy.

OBJECTIVES: This study sought to analyze the impact of the American College of Cardiology, American Heart Association, and Heart Rhythm Society (ACC/AHA/HRS) guidelines for cardiac resynchronization therapy with defibrillator (CRT-D) update on utilization and efficacy of CRT-D. BACKGROUND: In September 2012, the ACC/AHA/HRS guidelines for CRT-D were modified to include left bundle branch block (LBBB) as a Class I indication. METHODS: The IBM Watson MarketScan Database was queried between January 1, 2003, and December 31, 2018, for CRT-D implants or upgrades. The primary outcome was heart failure (HF) hospitalization following left ventricular lead implant. Secondary outcomes included all-cause mortality and device-related lead revision. RESULTS: A total of 27,238 patients were analyzed: 18,384 pre-update and 8,854 post-update. Mean age was 69 ± 11 years, 73% men, and 98% with history of HF hospitalization. The proportion of patients with LBBB increased from 29% to 55% (P < 0.001) after the update. Patients receiving CRT-D post-update demonstrated a greater prevalence of comorbidities, including atrial fibrillation (47% vs 40%; P < 0.001), diabetes mellitus (45% vs 39%; P < 0.001), chronic kidney disease (24% vs 15%; P < 0.001), and HF hospitalization in the year before CRT-D (40% vs 37%; P < 0.001). Despite greater baseline comorbidities, HF hospitalization significantly declined post-update (HR: 0.89; P < 0.001). Multivariate predictors of reduced HF hospitalization included angiotensin receptor neprilysin inhibitor prescription (HR: 0.48; P < 0.001) and presence of LBBB (HR: 0.71; P < 0.001). All-cause mortality was not significantly different between the 2 groups, and fewer lead revisions were noted post-update (0.6% vs 1.7%; P < 0.001). CONCLUSIONS: The revised 2012 guidelines led to an increased proportion of LBBB patients receiving CRT-D at the population-level. This change was associated with reduced HF hospitalization, despite broadening therapy to patients with more comorbid conditions.

Psychosocial Stress Exposure Disrupts Mammary Gland Development.

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8-25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.