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.

Loss of heme oxygenase 2 causes reduced expression of genes in cardiac muscle development and contractility and leads to cardiomyopathy in mice.

Obstructive sleep apnea (OSA) is a common breathing disorder that affects a significant portion of the adult population. In addition to causing excessive daytime sleepiness and neurocognitive effects, OSA is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not completely understood. Using exposure to intermittent hypoxia (IH) to mimic OSA, we have recently reported that mice exposed to IH exhibit endothelial cell (EC) activation, which is an early process preceding the development of cardiovascular disease. Although widely used, IH models have several limitations such as the severity of hypoxia, which does not occur in most patients with OSA. Recent studies reported that mice with deletion of hemeoxygenase 2 (Hmox2-/-), which plays a key role in oxygen sensing in the carotid body, exhibit spontaneous apneas during sleep and elevated levels of catecholamines. Here, using RNA-sequencing we investigated the transcriptomic changes in aortic ECs and heart tissue to understand the changes that occur in Hmox2-/- mice. In addition, we evaluated cardiac structure, function, and electrical properties by using echocardiogram and electrocardiogram in these mice. We found that Hmox2-/- mice exhibited aortic EC activation. Transcriptomic analysis in aortic ECs showed differentially expressed genes enriched in blood coagulation, cell adhesion, cellular respiration and cardiac muscle development and contraction. Similarly, transcriptomic analysis in heart tissue showed a differentially expressed gene set enriched in mitochondrial translation, oxidative phosphorylation and cardiac muscle development. Analysis of transcriptomic data from aortic ECs and heart tissue showed loss of Hmox2 gene might have common cellular network footprints on aortic endothelial cells and heart tissue. Echocardiographic evaluation showed that Hmox2-/- mice develop progressive dilated cardiomyopathy and conduction abnormalities compared to Hmox2+/+ mice. In conclusion, we found that Hmox2-/- mice, which spontaneously develop apneas exhibit EC activation and transcriptomic and functional changes consistent with heart failure.

Plasma proteomic analysis of association between atrial fibrillation, coronary microvascular disease and heart failure.

The clinical association between atrial fibrillation (AF), coronary microvascular disease (CMD) and heart failure with preserved ejection fraction (HFpEF) is highly prevalent, however the mechanism behind this association is not known. We hypothesized that plasma proteomic analysis can identify novel biomarkers and the mechanistic pathways in concomitant AF, CMD and HFpEF. To discover circulating biomarkers for the association between AF, CMD and HFpEF, an unbiased label-free quantitative proteomics approach was used in plasma derived from patients who underwent coronary physiology studies (n=18). Circulating proteins were analyzed by liquid chromatography-mass spectrometry and screened to determine candidate biomarkers of the concomitant AF, CMD and HFpEF. We identified 130 dysregulated proteins across the groups with the independent patient replicates. Among those, 35 proteins were candidate biomarkers of the association between AF, CMD and HFpEF. We found significantly elevated SAA1, LRG1 and APOC3 proteins in the coexistence of AF, CMD and HFpEF, whereas LCP1, PON1 and C1S were markedly downregulated in their associations. AF was associated with reduced LCP1, KLKB1 and C4A in these patients. Combined downregulation of PON1 and C1S was a marker of concurrent HFpEF and CMD. PON1 was associated with HFpEF while C1S was a marker of CMD. These proteins are related to inflammation, extra cellular remodeling, oxidative stress, and coagulation. In conclusion, plasma proteomic profile provides biomarkers and mechanistic insight into the association of AF, CMD and HFpEF. SAA1, LRG1, APOC3, LCP1, PON1 and C1S are candidate markers for the risk stratification of their associations and potential underlying mechanistic pathways.

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.

Impact of physiological pacing on functional mitral regurgitation in systolic dysfunction: Initial echocardiographic remodeling findings after His bundle pacing.

BACKGROUND: Although His bundle pacing (HBP) has been shown to improve left ventricular ejection fraction (LVEF), its impact on mitral regurgitation (MR) remains uncertain. OBJECTIVES: The aim of this study was to evaluate change in functional MR after HBP in patients with left ventricular (LV) systolic dysfunction. METHODS: Paired echocardiograms were retrospectively assessed in patients with reduced LVEF (<50%) undergoing HBP for pacing or resynchronization. The primary outcomes assessed were change in MR, LVEF, LV volumes, and valve geometry pre- and post-HBP. MR reduction was characterized as a decline in ≥1 MR grade post-HBP in patients with ≥grade 3 MR at baseline. RESULTS: Thirty patients were analyzed: age 68 ± 15 years, 73% male, LVEF 32% ± 10%, 38% coronary artery disease, 33% history of atrial fibrillation. Baseline QRS was 162 ± 31 ms: 33% left bundle branch block, 37% right bundle branch block, 17% paced, and 13% narrow QRS. Significant reductions in LV end-systolic volume (122 mL [73-152 mL] to 89 mL [71-122 mL], P = .006) and increase in LV ejection fraction (31% [25%-37%] to 39% [30%-49%], P < .001) were observed after HBP. Ten patients had grade 3 or 4 MR at baseline, with reduction in MR observed in 7. In patients with at least grade 3 MR at baseline, reduction in LV volumes, improved mitral valve geometry, and greater LV contractility were associated with MR reduction. Greater reduction in paced QRS width was present in MR responders compared to non-MR responders (-40% vs -25%, P = .04). CONCLUSIONS: In this initial detailed echocardiographic analysis in patients with LV systolic dysfunction, HBP reduced functional MR through favorable ventricular remodeling.

Atypical pathogens associated with cardiac implantable electronic device infections.

BACKGROUND: Cardiovascular implantable electronic device (CIED) infections are associated with significant morbidity and mortality making the identification of the causative organism critical. The vast majority of CIED infections are caused by Staphylococcal species. CIED infections associated with atypical pathogens are rare and have not been systematically investigated. The objective of this study is to characterize the clinical course, management and outcome in patients with CIED infection secondary to atypical pathogens. METHODS: Medical records of all patients who underwent CIED system extraction at the University of Chicago Medical Center between January 2010 and November 2020 were retrospectively reviewed to identify patients with CIED infection. Demographic, clinical, infection-related and outcome data were collected. CIED infections were divided into typical and atypical groups based on the pathogens isolated. RESULTS: Among 356 CIED extraction procedures, 130 (37%) were performed for CIED infection. Atypical pathogens were found in 5.4% (n = 7) and included Pantoea species (n = 2), Kocuria species (n = 1), Cutibacterium acnes (n = 1), Corynebacterium tuberculostearicum (n = 1), Corynebacterium striatum (n = 1), Stenotrophomonas maltophilia (n = 1), and Pseudozyma ahidis (n = 1). All patients with atypical CIED infections were successfully treated with total system removal and tailored antibiotic therapy. There were no infection-related deaths. CONCLUSIONS: CIED infections with atypical pathogens were rare and associated with good outcome if diagnosed early and treated with total system removal and tailored antimicrobial therapy. Atypical pathogens cultured from blood, tissue or hardware in patients with CIED infection should be considered pathogens and not contaminants.

The relationship between coronary microvascular dysfunction, atrial fibrillation and heart failure with preserved ejection fraction.

OBJECTIVE: Coronary microvascular dysfunction (CMD) is a new frontier in cardiovascular disease and an important contributor to myocardial ischemia. A high prevalence of CMD is shown in heart failure, however, the cause-and-effect relationship between CMD and atrial fibrillation (AF) is unknown. We hypothesize that CMD is associated with AF and increases susceptibility to the co-existence of AF and heart failure with preserved ejection fraction (HFpEF). METHODS: Our study examined the relationship between CMD, AF, and HFpEF in all patients who underwent invasive coronary physiology studies for assessment of chest pain or dyspnea. CMD was defined as impaired coronary flow reserve (CFR) without obstructive coronary disease. RESULTS: A total of 80 patients (mean age 60±12 years, 68.8% female, median follow up of 2.2 years) were studied. Patients with AF (61%) or HFpEF (62%), or both (71%) were more likely to have CMD than those patients without these conditions. Of the patients with AF and abnormal CFR, 91% had HFpEF. CMD was a predictor of AF with concomitant HFpEF (OR 4.38, P=0.02). Our clinical outcome analysis demonstrated that patients with CMD, AF or HFpEF had lower survival free of HF hospitalization than those patients without (P<0.05). AF (OR 5.5, P=0.02), diabetes, older age, female gender, and higher heart rate were predictors of CMD. CONCLUSION: CMD is highly prevalent in patients with AF with or without HFpEF. CMD is associated with poor clinical outcomes and the co-existence of AF and HFpEF. Understanding of the association between CMD and AF is important for developing an effective treatment strategy and the risk stratification for the prevention of AF in patients with CMD and vice versa.

Activation of AMP-Activated Protein Kinases Prevents Atrial Fibrillation.

Atrial fibrillation (AF) is common, yet there is no preventive therapy for AF. We tested the efficacy of AMP-activated protein kinase (AMPK) activators, metformin, and aspirin, in primary prevention of AF in cardiac-specific liver kinase B1 (LKB1) knockout (KO) mouse model of AF. Incidence of spontaneous AF was significantly reduced in treated KO mice with metformin (10 mg/kg/day) (8.3% in male and 10.3% in female) and aspirin (20 mg/kg/day) (29.4% in male and 21.4% in female) compared with untreated littermates (81% in male and 67% in female) at 8 weeks (p < 0.05). Prevention of AF was associated with activation of AMPK in treated mice and thereby improvement of mitochondrial function, gap junction proteins (connexin 40/43), and intra- and inter-cellular ultrastructure in atrial myocardium. Fibrosis was significantly less in treated mice atria. Pharmacological activation of AMPK is an effective upstream therapy for the primary prevention of AF in susceptible heart. Graphical abstract.

Prognostic value of cardiac magnetic resonance septal late gadolinium enhancement patterns for periaortic ventricular tachycardia ablation: Heterogeneity of the anteroseptal substrate in nonischemic cardiomyopathy.

BACKGROUND: Ventricular tachycardia (VT) from the anteroseptal subtype of nonischemic cardiomyopathy has a high probability of recurrence after catheter ablation. OBJECTIVE: The purpose of this study was to determine the predictive value of septal scar patterns by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) on ablation outcomes in patients with VT arising from an anteroseptal substrate. METHODS: Patients with periaortic VT arising from an anteroseptal substrate with preprocedural wideband LGE-CMR were divided into 2 groups by the degree of longitudinal septal LGE extension as full-length septal (≥80% anteroposterior length) or partial septal (<80% anteroposterior length). Septal LGE volumes were quantified in those with and without VT recurrence. RESULTS: Among 234 patients referred for scar-related VT ablation between 2017 and 2020, 25 patients (92% male; age 64 ± 8 years) and a total of 108 VTs were analyzed. A greater number of VT morphologies were induced in patients with full-length septal LGE compared to partial septal LGE (median [interquartile range]: 5 [3-9] vs 2 [1-4]; P = .005). Patients with VT recurrence had larger septal LGE volumes compared to those without recurrence (11.4 mL [8.8-13.9] vs 4.2 mL [0-9.5]; P = .012). At median follow-up of 16 months (5-22), overall freedom from VT recurrence was 52% and significantly higher in patients with partial septal LGE than in those with full-length septal LGE (80% vs 20%; P = .005). CONCLUSION: VT originating from an anteroseptal substrate is associated with heterogeneous patterns and extent of CMR septal scar. Preprocedural imaging may substratify this challenging patient population for the propensity for multiple induced VT morphologies and recurrence after catheter ablation.

Left ventricular summit arrhythmias with an abrupt V3 transition: Anatomy of the aortic interleaflet triangle vantage point.

BACKGROUND: While early precordial electrocardiographic (ECG) characteristics are useful to differentiate left-sided from the right-sided outflow tract ventricular arrhythmia (OTVA), few patterns predict an origin from the septal margin of the left ventricular (LV) summit. OBJECTIVE: The purpose of this study was to report mapping and ablation characteristics of a new ECG pattern with left bundle branch morphology and an abrupt R-wave transition in lead V3 (ATV3). METHODS: Over a 3-year period, 78 consecutive patients (mean age 57±15 years; 35% female) with OTVA were referred for mapping and ablation. Twenty patients (26%) exhibited an ATV3 pattern, of whom 65% failed prior ablation. RESULTS: Ninety-two percent of patients with ATV3 that underwent simultaneous epicardial and endocardial mapping demonstrated an intramural or epicardial site of origin. Eighty percent of OTVA with ATV3 was eliminated by ablation from the vantage point of the interleaflet triangle below the right-left coronary junction. The ATV3 pattern showed higher sensitivity, specificity, predictive value, and accuracy than validated ECG criteria (notch or "w" pattern in lead V1, qrS pattern in leads V1 through V3, and pattern break V2) for predicting successful ablation in the region of the anterior LV ostium. At 12±11 months, freedom from ventricular arrhythmia recurrence was 89% and 82% in the ATV3 and control groups, respectively. CONCLUSION: ATV3 is a simple and distinct ECG pattern indicative of a site of origin from the septal margin of the LV summit. The right-left aortic interleaflet triangle vantage point was effective to eliminate OTVA with ATV3 that overwhelmingly exhibited the earliest activation from the epicardium or mid-myocardium. Test characteristics for ATV3 were superior to ECG patterns validated for the anterior LV ostium.

Indirect and Direct Evidence for 3-D Activation During Left Atrial Flutter: Anatomy of Epicardial Bridging.

OBJECTIVES: This study sought to describe arrhythmia characteristics using ultra-high density (UHD) mapping of macro-re-entrant left atrial flutter (LAFL) which propagate via epicardial bridging (EB), and highlight regional anatomy that poses challenges to ablation. BACKGROUND: Three-dimensional propagation via EB may contribute to the maintenance and complexity of LAFL. METHODS: UHD activation maps of macro-re-entrant LAFL created with a mini-electrode basket catheter were analyzed between June 2015 and March 2020. EB was defined as a region of wave front discontinuity with focal activation distal to an activation gap. Regions of EB were correlated with anatomic structures known to have specialized epicardial bundles. Direct evidence of EB was obtained via percutaneous epicardial access (n = 22) with simultaneous epicardial recordings during endocardial activation gaps. RESULTS: Among 159 patients who underwent LA endocardial procedures with UHD mapping, 43 patients with 47 macro-re-entrant LAFLs were included in this analysis. Evidence of EB was present in 38% of LAFLs. Four anatomic areas of EB were observed: coronary sinus (17%), vein of Marshall (28%), Bachmann's region (33%), and region of the septopulmonary bundle (22%). All 47 LAFLs were successfully ablated. Percutaneous epicardial mapping yielded direct evidence for EB in 9 patients with LAFL (41%). At 23 ± 13 months, 70% remained free from recurrent LAFL. CONCLUSIONS: In a selected population, UHD mapping demonstrates evidence of EB in 38% of cases of LAFL involving 4 distinct epicardial anatomic regions. Identification of discontinuous 3-dimensional activation patterns with attention to correlative regional LA anatomy may reduce the incidence of ablation failures for complex re-entry.

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

BACKGROUND: Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava-right atrium during transvenous lead extraction is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with transvenous lead extraction difficulty. METHODS: Serial imaging of leads occurred before transvenous lead extraction using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty was calculated for each patient and compared with IVUS findings. RESULTS: One hundred fifty-eight vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, P<0.001) and median laser pulsations delivered (low=0 versus high grade=5852, P<0.001) were significantly higher in high-grade segments. Most patients with low lead extraction difficulty score had low ILA grades. Eighty-six percentage of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores. CONCLUSIONS: IVUS is a feasible imaging modality that may be useful in characterizing ILA in the superior vena cava-right atrium region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging. Graphic Abstract: A graphic abstract is available for this article.

Periaortic ventricular tachycardia in structural heart disease: Evidence of localized reentrant mechanisms.

BACKGROUND: The mechanisms for scar-related ventricular tachycardia (VT) originating from the periaortic region remain incompletely characterized. OBJECTIVE: The purpose of this study was to map the circuits responsible for periaortic VT in high resolution. METHODS: Cases with periaortic VT (2016-2020) were analyzed to characterize the substrate and mechanisms with multielectrode mapping. Periaortic VT was defined as low-voltage and/or deceleration zones within 2 cm of the left ventriculoaortic junction with a corresponding critical site during VT. RESULTS: Forty-nine periaortic monomorphic VTs were analyzed in 30 patients (25% of all patients with nonischemic cardiomyopathy). Isolated periaortic substrate was observed in 27% of patients, with 73% having concomitant scar, most commonly in the mid-septum (47%). Deceleration zones were equally prevalent on the septal and lateral portions of the periaortic region (87% vs 73%; P = .19). During activation mapping of VT (tachycardia cycle length 392 ± 105 ms), localized reentrant patterns of activation (14 mm [10-17 mm] × 10 mm [7-14 mm]) were demonstrated in 63% and 37% of VTs showed centrifugal activation, consistent with a focal breakout pattern. Ninety-three percent of VTs fulfilled criteria for a reentrant mechanism. Sixty-five percent of reentrant circuits had endocardial activation gaps within the tachycardia cycle length (3-dimensional circuitry), which were associated with higher rates of recurrence as compared with 2-dimensional complete circuits at 1 year (73% vs 37%; P = .028). CONCLUSION: Periaortic VTs were observed in 25% of patients with nonischemic cardiomyopathy and scar-related VT. For the first time, localized reentry confined to this anatomically challenging region was demonstrated as the predominant mechanism by high-resolution circuit activation mapping.

Atrial arrhythmias in patients with left ventricular assist devices.

PURPOSE OF REVIEW: Atrial arrhythmias commonly occur in patients with advanced heart failure with reduced ejection fraction (HFrEF) who require left ventricular assist devices (LVADs) implantation. This review summarizes the current literature regarding the incidence, prevalence, and predictors of atrial arrhythmias in LVAD patients and its impact on the clinical outcomes. Moreover, we review the mechanisms and management strategies of atrial arrhythmias in this population. RECENT FINDINGS: Atrial arrhythmias including atrial fibrillation, atrial flutter, and atrial tachycardia are highly prevalent in patients with advanced HFrEF before or after the LVAD implantation. Atrial arrhythmias have a significant impact on overall clinical outcome including survival, heart failure hospitalization, quality of life, thromboembolic events and resource utilization. Atrial fibrillation and other atrial arrhythmias frequently coexist in this population. In patients with atrial arrhythmias and LVAD, anticoagulation and cardiovascular implantable electronic devices should be closely monitored and managed to prevent thromboembolic events or inappropriate shocks. Rhythm and rate control strategies are comparable regarding overall clinical outcomes in this population. LVADs induce favorable atrial remodeling in patients with HFrEF. SUMMARY: Atrial arrhythmias are highly common in LVAD patients and have significant impact on overall clinical outcomes. Further studies are needed to determine optimal management and prevention of atrial arrhythmias in LVAD population.

Molecular Mechanism of the Association Between Atrial Fibrillation and Heart Failure Includes Energy Metabolic Dysregulation Due to Mitochondrial Dysfunction.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) commonly coexist, yet the molecular mechanisms of this association have not been determined. We hypothesized that an energy deficit due to mitochondrial dysfunction plays a significant role in pathogenic link between AF and HF. METHODS AND RESULTS: Myocardial energy metabolism and mitochondria were examined in atrial tissue samples from patients and mice (cardiac-specific LKB1 knock-out) with HF and/or AF. There was significant atrial energy (ATP) deficit in patients with HF (11.5±1.3 nmol/mg, n=10; vs without HF 17±3.8 nmol/mg, n=5, P = .032). AF was associated with further energy depletion (ATP 5.4±1.2 nmol/mg, n=9) in HF (P = .001) and metabolic stress (AMP/ATP 1.6±0.1 vs 0.7±0.2 in HF alone; P = .043). The left atrium demonstrated lower ATP than the right (P = .004). Mitochondrial dysfunction and remodeling caused ATP depletion with impaired oxidative phosphorylation complexes (succinate dehydrogenase and cytochrome c oxidase), increased reactive oxygen species, and mtDNA damage in mice and human atria with AF and HF. CONCLUSIONS: Molecular mechanisms of the association between HF and AF include an energy deficit due to mitochondrial dysfunction in atrial myocardium. Mitochondrial functional and structural remodeling in human and mouse atria is associated with energy metabolic dysregulation and oxidative stress that promote AF in HF and vice versa.

Impact of Atrial Fibrillation Ablation on Recurrent Hospitalization: A Nationwide Cohort Study.

OBJECTIVES: This study assessed the impact of atrial fibrillation (AF) ablation on hospitalization and antiarrhythmic drug use in the community setting. BACKGROUND: Despite the widespread increase in the use of catheter ablation to treat AF in the United States, the impact of ablation on arrhythmic, cardiovascular, and noncardiovascular hospitalizations remains unclear. METHODS: The national prospectively acquired Truven Health MarketScan data set (January 1, 2008 to December 31, 2014) was used to identify patients who underwent first time AF ablation with uninterrupted enrollment for 24 months (12 months pre-ablation and 12 months post-ablation). Multivariate logistic regression was used to determine predictors of hospitalization. RESULTS: Of 5,238 patients who underwent AF ablation for the first time, 2,720 patients with uninterrupted enrollment were analyzed (age 60 ± 10 years; 29% were women, 79% had hypertension, and 23% had heart failure [HF]). AF ablation was associated with significantly reduced all-cause hospitalization from 1,669 hospitalizations in the year before ablation to 1,034 hospitalizations in the year after ablation, which was driven primarily by a 56% reduction in arrhythmic hospitalization. Nonarrhythmic cardiovascular hospitalizations also declined through a 43% drop off in HF hospitalizations. Noncardiovascular hospitalization rates did not significantly change. Age younger than 55 years (odds ratio [OR]: 1.43; p < 0.001), obstructive sleep apnea (OR: 1.38; p < 0.001), and HF (OR: 1.29; p = 0.024) were multivariate predictors for decreased arrhythmic hospitalization. Rates of antiarrhythmic drug use also significantly declined post-procedure by 37.5% (p < 0.001). CONCLUSIONS: In this nationwide cohort, AF ablation was associated with significant decreases in arrhythmic and nonarrhythmic cardiovascular hospitalizations, which was driven by reductions in hospitalization for AF and HF.

Intracardiac Delineation of Septal Conduction in Left Bundle-Branch Block Patterns.

BACKGROUND: Septal activation in patients with left bundle-branch block (LBBB) patterns has not been described previously. We performed detailed intracardiac mapping of left septal conduction to assess for the presence and level of complete conduction block (CCB) in the His-Purkinje system. Response to His bundle pacing was assessed in patients with and without CCB in the left bundle. METHODS: Left septal mapping was performed with a linear multielectrode catheter in consecutive patients with LBBB pattern referred for device implantation (n=38) or substrate mapping (n=47). QRS width, His duration, His-ventricular (HV) intervals, and septal conduction patterns were analyzed. The site of CCB was localized to the level of the left-sided His fibers (left intrahisian) or left bundle branch. Patients with ventricular activation preceded by Purkinje potentials were categorized as having intact Purkinje activation. RESULTS: A total of 88 left septal conduction recordings were analyzed in 85 patients: 72 LBBB block pattern and 16 controls (narrow QRS, n=11; right bundle-branch block, n=5). Among patients with LBB block pattern, CCB within the proximal left conduction system was observed in 64% (n=46) and intact Purkinje activation in the remaining 36% (n=26). Intact Purkinje activation was observed in all controls. The site of block in patients with CCB was at the level of the left His bundle in 72% and in the proximal left bundle branch in 28%. His bundle pacing corrected wide QRS in 54% of all patients with LBBB pattern and 85% of those with CCB (94% left intrahisian, 62% proximal left bundle-branch). No patients with intact Purkinje activation demonstrated correction of QRS with His bundle pacing. CCB showed better predictive value (positive predictive value 85%, negative predictive value 100%, sensitivity 100%) than surface ECG criteria for correction with His bundle pacing. CONCLUSIONS: Heterogeneous septal conduction was observed in patients with surface LBBB pattern, ranging from no discrete block to CCB. When block was present, we observed pathology localized within the left-sided His fibers (left intrahisian block), which was most amenable to corrective His bundle pacing by recruitment of latent Purkinje fibers. ECG criteria for LBBB incompletely predicted CCB, and intracardiac data might be useful in refining patient selection for resynchronization therapy.