Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation.

BACKGROUND: Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. OBJECTIVES: To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. METHODS: A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. RESULTS: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04-1.36], p = 0.026; NT-proBNP: HR:1.19[1.06-1.35], p = 0.016; Ang2: HR:1.07[0.95-1.20], p = 0.283; BMP10: HR:1.09[0.96-1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29-1.90], p < 0.001 1.63], p = 0.097). CONCLUSIONS: The association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

Declining clinical benefit of ICD in heart failure patients: Temporal trend of mortality outcomes from randomized controlled trials.

BACKGROUND: The risk of sudden cardiac death in patients with heart failure has declined over time thanks to the sequential introduction of new treatments. However, current guidelines recommendations for implantable cardioverter-defibrillator (ICD) are based on randomized controlled trials (RCTs) carried out in the past three decades and their meta-analyses. To highlight potential changes over time in ICD clinical benefit in primary prevention of sudden cardiac death, we analyzed the temporal trends of RCT risk of mortality outcomes in this time frame. METHODS: By searching MEDLINE and the Cochrane Library electronic databases we identified seven RCTs (6095 patients enrolled between 1990 and 2014) on ICD versus contemporary standard medical therapy for sudden cardiac death prevention, in patients with chronic heart failure of ischemic and non-ischemic origin and reduced ejection fraction. Linear regression analysis was applied to identify the association between RCT mortality outcomes and time. RESULTS: Ordered according to the start of randomization, the trials showed a statistically significant (p=0.03) progressive decline in the baseline annualized event rate of sudden cardiac death in RCT control arms, and a significant (p=0.04) increase in the number of patients unresponsive to ICD treatment (i.e. patients experiencing sudden cardiac death in ICD arms). These two factors synergistically contributed to a significant (p<0.01) and progressive reduction in the clinical benefit of ICD, assessed by the number needed to treat for total mortality at 3 years. CONCLUSIONS: The clinical benefit of ICD, implanted according to the current guidelines, has significantly and progressively declined over time due to the reduction in sudden cardiac death risk and to the increase of ICD unresponsive patients.

Ventricular tachycardia-inducibility predicts arrhythmic events in post-myocardial infarction patients with low ejection fraction. A systematic review and meta-analysis.

BACKGROUND: Inducibility of ventricular arrhythmias at electrophysiological study (EPS) has long been suggested as predictive for subsequent arrhythmic events. Nevertheless, the usefulness of EPS in the clinical practice is still unclear. We performed a systematic review and meta-analysis to assess the predictive power of EPS in primary prevention of ventricular arrhythmias in post-myocardial infarction (MI) patients with left ventricular dysfunction. METHODS: MEDLINE and the Cochrane Library databases were systematically searched to identify studies, which analyzed EPS predictive value in post-MI patients with mean EF < 40% for the composite arrhythmic endpoint defined by: sudden cardiac death (SCD), aborted SCD, ventricular tachycardia (VT), ventricular fibrillation (VF), appropriate implantable cardioverter-defibrillator (ICD) interventions. RESULTS: Nine studies, evaluating 3959 patients with 647 arrhythmic events, were included in the meta-analyses. EPS showed a strong predictive power for the arrhythmic endpoint with a pooled odds ratio (OR) of 4.00 (95% confidence interval [CI]: 2.30-6.96) in the whole set of studies, albeit a high level of heterogeneity among studies. EPS predictive power was higher in studies where VT-inducibility was tested (OR 6.52; 95% CI: 2.30-18.44; sensitivity 0.65, specificity 0.78, and negative predictive value 0.94), versus those assessing VT/VF-inducibility (OR 2.09; 95% CI: 1.34-3.26). VT-inducibility was predictive even when assessed within one month after MI (OR 7.85; 95% CI: 3.67-16.80). CONCLUSIONS: Inducibility of ventricular arrhythmias at EPS is a strong predictor of the arrhythmic endpoint in post-MI patients with impaired EF, particularly when VT-inducibility is tested. EPS could help selecting the patients who can mostly benefit from ICD therapy.

Myocardial fibrosis predicts ventricular tachyarrhythmias.

Myocardial fibrosis is a common pattern in the setting of different heart diseases, and promotes ventricular tachyarrhythmias by creating a vulnerable substrate for reentrant activity and by favoring the emergence of triggers. Currently, late gadolinium enhancement (LGE) cardiac magnetic resonance is considered the reference method for the noninvasive assessment of ventricular fibrosis. Several studies and meta-analyses have shown that ventricular fibrosis detected by LGE is a powerful predictor of ventricular tachyarrhythmic events in ischemic, non-ischemic dilated cardiomyopathy and hypertrophic cardiomyopathy patients. Both the presence and extension of ventricular fibrosis were shown to correlate with the occurrence of ventricular arrhythmias and sudden cardiac death, irrespective of the grade of left ventricular dysfunction. Based on these results, the assessment of ventricular fibrosis has been suggested as a candidate marker to improve the decision making for implantable cardioverter-defibrillator therapy in patients with left ventricular dysfunction. These points will be discussed in the review.

Characterization of rate and regularity of ventricular response during atrial tachyarrhythmias. Insight on atrial and nodal determinants.

OBJECTIVE: Ventricular rate and regularity affect hemodynamic stability and are targets of rate control therapy in patients with atrial flutter (AFL) and atrial fibrillation (AF). Nevertheless, the characteristics and determinants of ventricular response during these atrial arrhythmias are poorly understood. This work aims to investigate the effects of changes in atrial activity and atrioventricular (AV) conduction patterns on ventricular response in patients with atrial tachyarrhythmias by a combined quantitative analysis of atrial and ventricular time series. APPROACH: Time series were determined in patients during 24 episodes of AFL and 13 episodes of AF. Ventricular response was characterized in terms of mean ventricular interval, time-domain variability parameters, and entropy-based irregularity measures (quadratic entropy rate, QSE, and coefficient of sample entropy, COSEn). Atrial activity was characterized in terms of mean atrial rate and variability. AV conduction was analyzed by AV synchrogram method, quantifying the stability of AV coupling and the average AV conduction ratio. The dependence of ventricular features on atrial/AV determinants was investigated by correlation analysis. MAIN RESULTS: The analysis showed ventricular response to display a wide spectrum of variability and irregularity features at changing atrial and AV properties. The ventricular interval was significantly correlated with the AV conduction ratio (Spearman correlation coefficient ρ = -0.76, p < 0.005), while it did not correlate with atrial rate. The variability and irregularity of ventricular response were influenced by both atrial and AV parameters. QSE and COSEn significantly increased at shorter atrial cycle lengths (ρ = -0.67 and -0.71, p < 0.005), at higher atrial variability (ρ = 0.80 and 0.77, p < 0.005), at reduced AV coupling (ρ = -0.91, p < 0.005) and at smaller AV conduction ratios (ρ = -0.65 and -0.52, p < 0.005). SIGNIFICANCE: The identification of the determinants of ventricular rate and regularity may have significant implications in the development of efficacious rate control strategies in patients with atrial tachyarrhythmias.

Heart Rate Turbulence Is a Powerful Predictor of Cardiac Death and Ventricular Arrhythmias in Postmyocardial Infarction and Heart Failure Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Heart rate turbulence (HRT) has been proposed as a candidate marker of altered autonomic tone, and some studies showed its prognostic value for both cardiac death (CD) and sudden death. Nevertheless, HRT is not currently used in the clinical practice. METHODS AND RESULTS: We performed a systematic review and meta-analysis of the predictive value of HRT for the end points of total mortality, CD, and fatal and nonfatal ventricular arrhythmias in postacute myocardial infarction and heart failure patients. MEDLINE and The Cochrane Library databases were systematically searched to identify studies, which analyzed the predictive value of abnormal HRT for the defined end points. Twenty studies (25 cohorts: 12 832 patients) were identified by the systematic review, and 15 studies (20 cohorts: 11 499 patients) were included in the meta-analyses. Abnormal HRT was a predictive marker for all the end points in heart failure patients and more markedly in postacute myocardial infarction patients, where 9 out of the 10 cohorts had an ejection fraction >30%. In postacute myocardial infarction patients, HRT had pooled risk ratios of 3.53 (95% confidence interval [CI], 2.54-4.90), 4.82 (95% CI, 3.12-7.45), and 4.48 (95% CI, 3.04-6.60), and positive likelihood ratios of 3.5 (95% CI, 2.6-4.8), 4.1 (95% CI, 3.0-5.7), and 2.7 (95% CI, 2.2-3.3) for total mortality, CD, and arrhythmic events, respectively. The combination of abnormal HRT and T-wave alternans (5 cohorts: 1516 patients) increased the predictive power for CD and arrhythmic events. CONCLUSIONS: HRT is a powerful predictor of both CD and arrhythmic events, particularly in postacute myocardial infarction patients with ejection fraction >30%. HRT power increases in combination with T-wave alternans analysis.

Myocardial Fibrosis Assessment by LGE Is a Powerful Predictor of Ventricular Tachyarrhythmias in Ischemic and Nonischemic LV Dysfunction: A Meta-Analysis.

OBJECTIVES: The authors performed a meta-analysis to evaluate the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance for ventricular tachyarrhythmia in ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients with ventricular dysfunction. BACKGROUND: The use of LGE to detect myocardial fibrosis and its related arrhythmic substrate is well established. Several recent studies have described the predictive value of LGE for ventricular tachyarrhythmias; however, their validity is limited by small sample size and low number of events. METHODS: MEDLINE and the Cochrane Library electronic databases were systematically searched to identify studies that applied LGE in ICM and NICM patients with ventricular dysfunction and reported arrhythmic clinical outcomes (sudden death, aborted sudden death, ventricular tachycardia, ventricular fibrillation, and appropriate implantable cardioverter-defibrillator [ICD] therapy, including antitachycardia pacing). A meta-analysis was performed to determine pooled odds ratios (ORs) for these arrhythmic events. RESULTS: Nineteen studies that evaluated 2,850 patients with 423 arrhythmic events over a mean/median follow-up of 2.8 years were identified. The composite arrhythmic endpoint was reached in 23.9% of patients with a positive LGE test (annualized event rate of 8.6%) versus 4.9% of patients with a negative LGE test (annualized event rate of 1.7%; p < 0.0001). LGE correlated with arrhythmic events in the different patient groups. In the overall population, the pooled OR was 5.62 (95% confidence interval [CI]: 4.20 to 7.51), with no significant differences between ICM and NICM patients. In a subgroup of 11 studies (1,178 patients) with mean ejection fraction (EF) ≤30%, the pooled OR for the arrhythmic events increased to 9.56 (95% CI: 5.63 to 16.23), with a negative likelihood ratio of 0.13 (95% CI: 0.06 to 0.30). CONCLUSIONS: LGE is a powerful predictor of ventricular arrhythmic risk in patients with ventricular dysfunction, irrespective of ICM and NICM etiology. The prognostic power of LGE is particularly strong in patients with severely depressed EF, which suggests its potential to improve patient selection for ICD implantation.

Improving the appropriateness of sudden arrhythmic death primary prevention by implantable cardioverter-defibrillator therapy in patients with low left ventricular ejection fraction. Point of view.

It is generally accepted that the current guidelines for the primary prevention of sudden arrhythmic death, which are based on ejection fraction, do not allow the optimal selection of patients with low left ventricular ejection fraction of ischemic and nonischemic etiology for implantation of a cardioverter-defibrillator. Ejection fraction alone is limited in both sensitivity and specificity. An analysis of the risk of sudden arrhythmic death with a combination of multiple tests (ejection fraction associated with one or more arrhythmic risk markers) could partially compensate for these limitations. We propose a polyparametric approach for defining the risk of sudden arrhythmic death using ejection fraction in combination with other clinical and arrhythmic risk markers (i.e. late gadolinium enhancement cardiac magnetic resonance, T-wave alternans, programmed ventricular stimulation, autonomic tone, and genetic testing) that have been validated in nonrandomized trials. In this article, we examine these approaches to identify three subsets of patients who cannot be comprehensively assessed by the current guidelines: patients with ejection fraction of 35% or less and a relatively low risk of sudden arrhythmic death despite the ejection fraction value; patients with ejection fraction of 35% or less and high competitive risk of death due to evolution of heart failure or noncardiac causes; and patients with ejection fraction between 35 and 45% with relatively high risk of sudden arrhythmic death despite the ejection fraction value.

Atrial fibrillation and NPPA gene p.S64R mutation: are cardiologists helpless spectators of healthy mutation carriers?

AIMS: Heterozygous p.(Ser64Arg) mutation in the natriuretic peptide precursor A gene has been associated with atrial fibrillation in the presence of common single nucleotide polymorphisms (rs10033464 and rs2200733; 4q25) that would act as modifiers. METHODS: We screened natriuretic peptide precursor A gene in 583 individuals and identified three unrelated carriers of the p.(Ser64Arg) mutation (0.5%). RESULTS: Only one of the three mutation carriers had episodes of atrial fibrillation. Cascade screening of the three families identified seven additional mutation carriers, none showing atrial fibrillation. The patients with atrial fibrillation also carried the rs2200733, which was however found in four additional nonatrial fibrillation family members and carriers of the p.(Ser64Arg). The prevalence of atrial fibrillation in p.(Ser64Arg) carriers was 10% and in those combining the mutation with the risk single nucleotide polymorphisms was 20%. In the unique mutated patient with atrial fibrillation, the arrhythmias was refractory to both pharmacological and ablation treatment, during 16 years of follow-up; his electrophysiological phenotype was characterized by short atrial cycle lengths with a median value of 131 ms that suggests shortening of atrial action potential. CONCLUSION: The prevalence of p.(Ser64Arg) mutation is low in the general population as is the prevalence of atrial fibrillation in mutation carriers (1/10). Atrial fibrillation in the affected mutated patient was lone at onset and progressively evolved with peculiar electrophysiological patterns.

Cardiac Remodeling, Circulating Biomarkers and Clinical Events in Patients with a History of Atrial Fibrillation. Data from the GISSI-AF Trial.

PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia and has an increasing impact on public health because of its morbidity and mortality. Clinical and diagnostic tests to predict the recurrence of arrhythmia and clinical events before AF becomes permanent are still an open issue. METHODS: 307 out of 1442 patients in sinus rhythm, at high risk of recurrence of AF enrolled in the GISSI-AF study, participated in a substudy with echocardiographic and biohumoral evaluation at baseline and at 12-month follow-up. The relations between biomarker concentrations and echocardiographic parameters with study endpoints in 1 year, were analysed by a stepwise multivariable Cox model (entry criteria p < 0.5 and stay criteria p < 0.2). RESULTS: The echocardiographic variables, cardiac markers and clinical variables considered in the statistical model indicated a higher concentration of NT-proBNP at baseline as the strongest factor related to time of first AF recurrence (HR 1.42; 95 %CI 1.23-1.46), first CV hospitalization (HR 1.58; 95 %CI 1.31-1.92) and increasing duration of recurrent AF (OR 2.16; 95 %CI 1.52-3.08). Valsartan treatment was not related to clinical events. CONCLUSIONS: In patients in sinus rhythm with a history of AF a higher concentration of NT-proBNP at baseline was the strongest independent risk factor for first AF recurrence and its duration, and for the first hospital admission for cardiovascular reasons.

[Remarks on polyparametric assessment of sudden death risk for primary prevention ICD implantation in patients with left ventricular dysfunction of ischemic and non ischemic etiology. Italian Association of Hospital Cardiologists (ANMCO) Experts Position Paper]. / Considerazioni su una valutazione poliparametrica nella stratificazione del rischio di morte improvvisa per l'indicazione all'impianto di cardioverter-defibrillatore in prevenzione primaria, nella disfunzione ventricolare sinistra di origine ischemica e non ischemica. Position paper dell'Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO).

It is generally recognized that current guidelines, based on ejection fraction criteria, do not allow appropriate selection of patients for implantable cardioverter-defibrillator (ICD) therapy in the primary prevention of sudden death, thus hindering the optimal use of ICD in patients with left ventricular dysfunction of ischemic and nonischemic etiology. Ejection fraction alone has limitations in both sensitivity and specificity. Assessment of the risk for sudden death using a combination of multiple tests (ejection fraction associated with one or more different arrhythmic risk markers) could partially compensate for these limitations. In this position paper, the potential usefulness of a polyparametric assessment using some of the most investigated risk markers of sudden death is discussed, including late gadolinium enhancement cardiac magnetic resonance, programmed ventricular stimulation, T-wave alternans, autonomic tone, biomarkers, and genetic testing.

Diabetes mellitus as risk factor for atrial fibrillation hospitalization: Incidence and outcomes over nine years in a region of Northern Italy.

AIMS: Diabetes mellitus (DM) and atrial fibrillation (AF) are worldwide public health challenges and major causes of death and cardiovascular events. The association between DM and AF is controversial in literature and data on outcomes of individuals with both diseases have not been evaluated in population studies. We tested the hypothesis that DM is independently associated to AF hospitalization and assessed the risk of stroke and mortality in people with both conditions. METHODS: We conducted a population-based cohort-study of DM patients and their corresponding controls identified in a administrative health database of the Lombardy Region. Both cohorts were followed for nine years. A multivariable Cox proportional-hazards-regression model was used to estimate the hazard ratio (HR) for first hospitalization for AF and for clinical outcomes. RESULTS: Out of 9,061,258 residents, 285,428 (3.14%) DM subjects were identified, mean age 65.8±15 years, 49% were women. The cumulative incidence of AF in DM was 10.4% vs. 7.4% in non-DM. DM was a risk factor for AF (HR 1.32, 95% CI 1.30-1.34; p<0.0001). Oral anticoagulants were prescribed in 34.8% of DM patients with AF. DM associated with AF, presented the highest HR for stroke: 2.63; 95% CI 2.47-2.80 and for total death, HR 2.41; 95% CI 2.36-2.47. CONCLUSIONS: In this population study, DM was an independent risk factor for AF hospitalization. DM patients with AF had the highest risk of stroke and total mortality. Early identification of AF and a structured plan to optimize the comprehensive management of DM and AF patients is mandatory.