Comparison of electrogram characteristics in persistent atrial fibrillation.

INTRODUCTION: Multiple analysis techniques evaluate electrograms during atrial fibrillation (AF), but none have been established to guide catheter ablation. This study compares electrogram properties recorded from multiple right (RA) and left atrial (LA) sites. METHODS: Multisite LA/RA mapping (281 ± 176/239 ± 166 sites/patient) was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (n = 32) or redo-AF ablation (n = 10). All electrogram recordings were visually reviewed and artifactual signals were excluded leaving a total of 21 846 for analysis. Electrogram characteristics evaluated were cycle length (CL), amplitude, Shannon's entropy (ShEn), fractionation interval, dominant frequency, organizational index, and cycle length of most recurrent morphology (CLR ) from morphology recurrence plot analysis. RESULTS: Electrogram characteristics were correlated to each other. All pairwise comparisons were significant (p < .001) except for dominant frequency and CLR (p = .59), and amplitude and dominant frequency (p = .38). Only ShEn and fractionation interval demonstrated a strong negative correlation (r = -.94). All other pairwise comparisons were poor to moderately correlated. The relationships are highly conserved among patients, in the RA versus LA, and in those undergoing initial versus redo ablations. Antiarrhythmic drug therapy did not have a significant effect on electrogram characteristics, except minimum ShEn. Electrogram characteristics associated with ablation outcome were shorter minimum CLR , lower minimum ShEn, and longer mimimum CL. There was minimal overlap between the top 10 sites identified by one electrogram characteristic and the top 10 sites identified by the other 10 characteristics. CONCLUSION: Multiple techniques can be employed for electrogram analysis in AF. In this analysis of eight different electrogram characteristics, seven were poorly to moderately correlated and do not identify similar locations. Only some characteristics were predictive of ablation outcome. Further studies to consider electrogram properties, perhaps in combination, for categorizing and/or mapping AF are warranted.

Epicardial fat thickness in type 2 diabetes outpatient care.

BACKGROUND AND AIM: Visceral fat is an independent predictor of the cardiovascular risk in subjects with type 2 diabetes (T2DM), but it is rarely assessed during an outpatient visit. Epicardial fat (EAT), the visceral fat of the heart, plays a role in coronary artery disease (CAD). EAT thickness can be clinically assessed with standard ultrasound. In this study we sought to evaluate the association of ambulatory ultrasound measured EAT thickness with CAD in asymptomatic well controlled T2DM subjects on metformin monotherapy during outpatient visits. METHODS AND RESULTS: This was single center, pragmatic study in 142 T2DM patients. Each subject underwent baseline ultrasound EAT thickness measurement, anthropometric and biomarkers. The incidence of CAD was detected after 1 year. At baseline, HbA1c was 6.7 % and BMI 34.9 kg/m2, EAT thickness was 8.3 ± 2.3 in women and 9.4 ± 2.4 mm in men, higher than threshold values for high cardiovascular risk. In multivariate models, EAT was the only statistically significant correlate of CAD at 1-year f/u (p = 0.04). CONCLUSIONS: Point of care ultrasound measured EAT thickness is a good correlate of CAD in well controlled and asymptomatic T2DM subjects on metformin monotherapy. EAT thickness predicted CAD better than traditional risk factors, such as BMI, HbA1c, age, blood pressure or duration of diabetes.

Contemporary outcomes of acute ischemic stroke in atrial fibrillation patients on anticoagulation.

BACKGROUND: Long-term anticoagulation (AC) therapy reduces the risk of stroke in patients with Atrial Fibrillation (AF). However, data on the impact of AC on in-hospital stroke outcomes is lacking. METHODS: The National Inpatient Sample was used to identify adult inpatients with AF and a primary diagnosis of ischemic stroke between 2016 and 2020. Data was stratified between AC users and nonusers. A multivariate regression model was used to describe the in-hospital outcomes, adjusting for significant comorbidities. RESULTS: A total of 655,540 hospitalizations with AF and a primary hospitalization diagnosis of ischemic stroke were included, of which 194,560 (29.7 %) were on long-term AC. Patients on AC tended to be younger (mean age, 77 vs. 78), had a higher average CHA2DS2VASc score (4.48 vs. 4.20), higher rates of hypertension (91 % vs. 88 %), hyperlipidemia (64 % vs. 59 %), and heart failure (34 % vs. 30 %) compared to patients not on long-term AC. Use of AC was associated with decreased in-hospital mortality (aOR [95 % CI]: 0.62 [0.60-0.63]), decreased stroke severity (mean NIHSS, 8 vs. 10), decreased use of tPA (aOR 0.42 [0.41-0.43]), mechanical thrombectomy (aOR 0.85 [0.83-0.87]), intracranial hemorrhage (aOR 0.69 [0.67-0.70]), gastrointestinal bleeding (aOR 0.74 [0.70-0.77]), and discharge to skilled nursing facilities (aOR 0.90 [0.89-0.91]), compared to patients not on AC (P<0.001 for all comparisons). CONCLUSION: Among patients with AF admitted for acute ischemic stroke, AC use prior to stroke was associated with decreased in-hospital mortality, decreased stroke severity, decreased discharge to SNF, and fewer stroke-related and bleeding complications.

Effects of catheter ablation of atrial fibrillation on the biomarker profile.

BACKGROUND: Following catheter ablation for atrial fibrillation (AF), there are dynamic changes in the atrial myocardium associated with damage to and necrosis of atrial tissue and other procedure related changes in rhythm and anticoagulation. Early time-dependent changes in biomarkers of necrosis, inflammation, and coagulation have been reported. This study examines mid-term (4-8 weeks post-ablation) changes in biomarkers and explores their ability to predict AF recurrence at one-year. METHODS: Twenty-seven patients (mean age 65.4 ± 9.7 years, 30% female) undergoing catheter ablation for AF had peripheral venous blood samples obtained at the time of ablation and 4-8 weeks later. All samples were processed to obtain plasma which was frozen for subsequent analysis. Coagulation studies were performed at the Northwestern Special Hemostasis Laboratory: VWF, ADAMTS13, PAI-1, D-dimer, and TAT complexes. A commercial lab analyzed samples for CRP, cystatin C, fibrinogen, galectin, IL-6, MMP-2, myoglobin, NT-proBNP, PAI-1, TIMP-1, TIMP-2, TPA, and VWF. RESULTS: Significant changes were noted with higher levels of ADAMTS13 (p < 0.0001), fibrinogen (p = 0.004), MMP-2 (p = 0.0002), TIMP-2 (p = 0.003), and TPA (p = 0.001) compared to lower levels of TAT (p < 0.0001) and NT-proBNP (p = 0.0001) at follow up post-ablation. One year after ablation, AF had recurred in 11/26 (42%) of patients. None of the biomarker changes predicted the 1-year outcome, and there was no significant association with the use of warfarin versus rivaroxaban. CONCLUSION: In patients undergoing catheter ablation for AF, there were significant changes in pre- vs post-ablation levels of multiple biomarkers. However, these changes were not associated with 1-year outcome of AF recurrence.

Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

AIMS: The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks. METHODS AND RESULTS: The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability. CONCLUSIONS: We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.

Carvedilol and exercise combination therapy improves systolic but not diastolic function and reduces plasma osteopontin in Col4a3-/- Alport mice.

There are currently no Food and Drug Administration-approved treatments for heart failure with preserved ejection fraction (HFpEF). Here we compared the effects of exercise with and without α/ß-adrenergic blockade with carvedilol in Col4a3-/- Alport mice, a model of the phenogroup 3 subclass of HFpEF with underlying renal dysfunction. Alport mice were assigned to the following groups: no treatment control (n = 29), carvedilol (n = 11), voluntary exercise (n = 9), and combination carvedilol and exercise (n = 8). Cardiac function was assessed by echocardiography after 4-wk treatments. Running activity of Alport mice was similar to wild types at 1 mo of age but markedly reduced at 2 mo (1.3 ± 0.40 vs. 4.5 ± 1.02 km/day, P < 0.05). There was a nonsignificant trend for increased running activity at 2 mo by carvedilol in the combination treatment group. Combination treatments conferred increased body weight of Col4a3-/- mice (22.0 ± 1.18 vs. 17.8 ± 0.29 g in untreated mice, P < 0.01), suggesting improved physiology, and heart rates declined by similar increments in all carvedilol-treatment groups. The combination treatment improved systolic parameters; stroke volume (30.5 ± 1.99 vs. 17.8 ± 0.77 µL, P < 0.0001) as well as ejection fraction and global longitudinal strain compared with controls. Myocardial performance index was normalized by all interventions (P < 0.0001). Elevated osteopontin plasma levels in control Alport mice were significantly lowered only by combination treatment, and renal function of the Alport group assessed by urine albumin creatinine ratio was significantly improved by all treatments. The results support synergistic roles for exercise and carvedilol to augment cardiac systolic function of Alport mice with moderately improved renal functions but no change in diastole.NEW & NOTEWORTHY In an Alport mouse model of heart failure with preserved ejection fraction (HFpEF), exercise and carvedilol synergistically improved systolic function without affecting diastole. Carvedilol alone or in combination with exercise also improved kidney function. Molecular analyses indicate that the observed improvements in cardiorenal functions were mediated at least in part by effects on serum osteopontin and related inflammatory cytokine cascades. The work presents new potential therapeutic targets and approaches for HFpEF.

Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.

Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease.

AIMS: To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD). METHODS AND RESULTS: The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009]. CONCLUSION: For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

Network meta-analysis of His bundle, biventricular, or right ventricular pacing as a primary strategy for advanced atrioventricular conduction disease with normal or mildly reduced ejection fraction.

INTRODUCTION: Although right ventricular pacing (RVP) may impair ventricular function, it is commonly used for advanced atrioventricular block (AVB) and normal or mildly reduced ejection fraction (EF). We aimed to compare His bundle pacing (HBP), biventricular pacing (BiVP), and RVP for advanced AVB in patients with normal or mildly reduced EF. METHODS AND RESULTS: MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, Scopus, and Web of Science were searched. Outcomes were all-cause death, heart failure hospitalizations (HFH), EF, left ventricular volumes, 6-minute walk test, and QRS duration. HBP or BiVP was compared with RVP. Subsequently, network meta-analysis compared the three pacing options. Our protocol was registered in PROSPERO (CRD42018094132). Six studies compared BiVP and RVP (704 vs 614 patients) and four compared HBP and RVP (463 vs 568 patients). Follow-up was 6 months to 5 years. There was significantly lower mortality and HFH with HBP or BiVP as compared with RVP (odds ratio [OR], 0.66, [0.51-0.85], P = .002; OR, 0.61 [0.45-0.82], P < .001, respectively]. HBP or BiVP also showed significant increase in EF and decrease in QRS duration (mean difference [MD], 5.27 [3.86-6.69], P < .001; MD -42.2 [-51.2 to -33.3], P < .001, respectively). In network meta-analysis, HBP and BiVP were associated with significantly improved survival compared to RVP, with surface under the cumulative ranking curve (SUCRA) probability of 79.4%, 69.4%, and 1.2% for HBP, BiVP, and RVP, respectively. For HFH, SUCRA probability was 91.5%, 57.2%, and 1.3%, respectively. CONCLUSION: HBP or BiVP were the superior strategies to reduce all-cause death and HFH for advanced AVB with normal or mildly reduced EF, with no significant difference between BiVP and HBP.

Disparities and Temporal Trends in the Use of Anticoagulation in Patients With Ischemic Stroke and Atrial Fibrillation.

Background and Purpose- Ischemic stroke (IS) secondary to atrial fibrillation (AF) is largely preventable with the use of anticoagulation. We sought to identify race-ethnicity and sex disparities with the use of direct oral anticoagulants (DOACs), aspirin, and warfarin in IS patients with AF and to identify temporal trends in the utilization of these medications. Methods- The FLiPER-AF Stroke Study (Florida Puerto Rico Atrial Fibrillation) included 24 040 IS cases enrolled in the Florida-Puerto Rico Collaboration to Reduce Stroke Registry from 2010 to 2016. Multivariable logistic regression models were performed to evaluate the effect of race-ethnicity and sex on utilization of DOACs, aspirin, and warfarin for stroke prevention in AF after adjustment for sociodemographic, hospital, and clinical factors. Results- Among 24 040 IS cases, 54% were women and 10% black, 12% FL-Hispanics, 4% PR-Hispanic, and 74% whites. From 2010 to 2016, DOAC use increased from 0% to 36%, warfarin use decreased from 51% to 17%, and aspirin use remained relatively stable (42%-40%). After adjustment, blacks had higher odds of warfarin (odds ratio, 1.22; 95% CI, 1.07-1.40) prescription at discharge compared with whites. Men had higher rates of aspirin (42.1% versus 38.8%), warfarin (33.6% versus 28.9%), and DOAC (21.3% versus 19.3%) use compared with women. After adjustment, women had lower odds of being discharged on aspirin (odds ratio, 0.92; 95% CI, 0.86-0.98) or warfarin (odds ratio, 0.91; 95% CI, 0.84-0.99). There was no sex difference in use of DOACs. Conclusions- Our study confirmed the increasing use of DOACs, downtrending use of warfarin, whereas aspirin use remained similar over the years. There are sex and race-ethnicity disparities in anticoagulation use in IS patients with AF. It is critical to understand underlying drivers of these disparities to develop better practice strategies for stroke prevention in patients with AF. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03627806.

A meta-analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease.

INTRODUCTION: The electrophysiologic impact of cell-based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta-analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). METHODS AND RESULTS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero-events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow-up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. CONCLUSION: Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.

The additive role of echocardiography in the screening for sudden death.

BACKGROUND: A clinically based sudden cardiac death (SCD) risk score has predictive value. Echocardiographic parameters predict SCD. Our aim was to evaluate the effect of adding echocardiographic parameters to the clinical SCD risk score for the prediction of all-cause mortality. METHODS: We conducted a retrospective cohort of screening echocardiograms performed on primary care patients. We calculated the SCD risk score and added the left ventricular (LV) mass index, LV hypertrophy, diastolic dysfunction, and LV ejection fraction (EF). We calculated the c-statistic, net reclassification index (NRI), and Hosmer-Lemeshow chi-square for the SCD score alone or combined with each echocardiographic parameter in predicting all-cause mortality. RESULTS: We included 6447 primary care patients who underwent a screening echocardiogram and had a SCD score. The c-statistic of the SCD score for mortality was 0.61; 95% CI 0.58-0.62 and the c-statistic for the score combined with LV mass index increased to 0.64; 95% CI 0.63-0.65 and for the score combined with LVEF, the c-statistic was 0.64;95% CI 0.63-0.67. When diastolic dysfunction and LV hypertrophy were added to the SCD score, the c-statistic did not significantly change (P > 0.05). The NRI for the addition of LV mass index and LVEF was 0.52 ± 0.02, and the Hosmer-Lemeshow statistic was nonsignificant (P > 0.05). CONCLUSIONS: Adding LV mass index or LVEF to the SCD risk score improves the ability to predict mortality, but in the primary care setting, the improvement is small and underscores the challenge of SCD prediction and prevention in the community.

Sudden Death Risk-Stratification in 2018-2019: The Old and the New.

Sudden Cardiac Death (SCD) is a major public health issue, accounting for half of all cardiovascular deaths world-wide. The implantable cardioverter-defibrillator (ICD) has been solidified as the cornerstone therapy in primary prevention of SCD in ischaemic and non-ischaemic cardiomyopathy. However, what has become increasingly clear is that the left ventricular ejection fraction (LVEF) is an inadequate tool to select patients for a prophylactic ICD, despite its widespread use for this purpose. Use of LVEF alone has poor specificity for arrhythmic versus non-arrhythmic death. In addition, the vast majority of sudden deaths occur in patients with more preserved cardiac function. Alternate predictors of sudden death include electrophysiology study, non-invasive markers of electrical instability, myocardial fibrosis, genetic and bio-markers. The challenge for the future is finding a risk stratification test, or combination of tests, that adequately select patients at high risk of SCD with low competing risk of non-sudden death.

Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy: The Past, Present, and Future.

Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy (DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.

Constitutive Expression of a Dominant-Negative TGF-ß Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate.

RATIONALE: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-ß (TGF-ß) signaling is thought to be intricately involved in creation of atrial fibrosis. OBJECTIVE: We hypothesized that gene-based expression of dominant-negative type II TGF-ß receptor (TGF-ß-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF. Because AF electrograms are thought to reflect AF substrate, we further hypothesized that TGF-ß-RII-DN would lead to increased fractionation and decreased organization of AF electrograms. METHODS AND RESULTS: Twenty-one dogs underwent injection+electroporation in the posterior left atrium of plasmid expressing a dominant-negative TGF-ß type II receptor (pUBc-TGFß-DN-RII; n=9) or control vector (pUBc-LacZ; n=12), followed by 3 to 4 weeks of right ventricular tachypacing (240 bpm). Compared with controls, dogs treated with pUBC-TGFß-DN-RII demonstrated an attenuated increase in conduction inhomogeneity, flattening of restitution slope and decreased duration of induced AF, with AF electrograms being more fractionated and less organized in pUBc-TGFß-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, p-SMAD2/3 and p-ERK1/2. CONCLUSIONS: Targeted gene-based reduction of TGF-ß signaling in the posterior left atrium-with resulting decrease in replacement fibrosis-led to beneficial remodeling of both conduction and restitution characteristics of the posterior left atrium, translating into a decrease in AF and increased complexity of AF electrograms. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

ß-blocker dosage and outcomes after acute coronary syndrome.

BACKGROUND: Although ß-blockers increase survival in acute coronary syndrome (ACS) patients, the doses used in trials were higher than doses used in practice, and recent data do not support an advantage of higher doses. We hypothesized that rates of major adverse cardiac events (MACE), all-cause death, myocardial infarction, and stroke are equivalent for patients on low-dose and high-dose ß-blocker. METHODS: Patients admitted to Intermountain Healthcare with ACS and diagnosed with ≥70% coronary stenosis between 1994 and 2013 were studied (N = 7,834). We classified low dose as ≤25% and high dose as ≥50% of an equivalent daily dose of 200 mg of metoprolol. Multivariate analyses were used to test association between low-dose versus high-dose ß-blocker dosage and MACE at 0-6 months and 6-24 months. RESULTS: A total of 5,287 ACS subjects were discharged on ß-blockers (87% low dose, 12% high dose, and 1% intermediate dose). The 6-month MACE outcomes rates for the ß-blocker dosage (low versus high) were not equivalent (P = .18) (hazard ratio [HR] = 0.76; 95% CI, 0.52-1.10). However, subjects on low-dose ß-blocker therapy did have a significantly decreased risk of myocardial infarction for 0-6 months (HR = 0.53; 95% CI, 0.33-0.86). The rates of MACE events during the 6-24 months after presentation with ACS were equivalent for the 2 doses (P = .009; HR = 1.03 [95% CI, 0.70-1.50]). CONCLUSIONS: In ACS patients, rates of MACE for high-dose and low-dose ß-blocker doses are similar. These findings question the importance of achieving a high dose of ß-blocker in ACS patients and highlight the need for further investigation of this clinical question.

Surface ECG f Wave Analysis at Initial Onset of Paroxysmal and Persistent Atrial Fibrillation.

INTRODUCTION: Dominant frequency (DF) analysis of electrocardiograms (ECGs) from patients with paroxysmal (PAF) and persistent (PeAF) atrial fibrillation has identified higher DFs in PeAF. We therefore hypothesized that among patients initially presenting to the emergency department (ED) with new onset AF, surface ECG features could differentiate PeAF from PAF. METHODS AND RESULTS: Initial 12-lead ECGs from patients presenting to the ED with a first episode of symptomatic AF were analyzed. Following QRS-T subtraction, fast Fourier transform (FFT) analysis of the AF fibrillatory waves was performed to measure DF and organization index (OI). Median DF of all leads and the DF in the lead with maximum OI were determined. Maximum f wave amplitude and vector magnitudes were measured. One hundred sixty-one patients (age 59 ± 16 years, 68% men) were included in this analysis, of whom 96 (58%) spontaneously converted to sinus rhythm within 7 days (PAF group). The remaining 65 patients underwent cardioversion or remained in AF (PeAF group). ECG features (DF, OI, f wave amplitude, and vector magnitude) did not differ among PAF and PeAF patients. CONCLUSIONS: ECG features (DF, OI, amplitude, vector magnitude) do not differ among patients with PAF versus PeAF when the ECGs are obtained at the initial onset of symptoms. Thus, prior data showing higher DF in PeAF likely reflect electrophysiologic remodeling rather than a marker for any specific type of AF or extent of underlying substrate.

Sudden cardiac death risk stratification.

Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized.

Ranolazine reduces atrial fibrillatory wave frequency.

AIMS: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. METHODS AND RESULTS: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). CONCLUSION: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF.