Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.

Cardiology of the future: xenotransplantation with porcine heart.

The reduced availability of human donor hearts compared with the needs of patients with advanced heart failure refractory to medical therapy has promoted the search for therapeutic alternatives to cardiac allografts. Porcine heart xenotransplantation represents one of the most promising frontiers in this field today. From the first researches in the 1960s to today, the numerous advances achieved in the field of surgical techniques, genetic engineering and immunosuppression have made it possible at the beginning of 2022 to carry out the first swine-to-human heart transplant, attaining a survival of 2 months after surgery. The main intellectual and experimental stages that have marked the history of xenotransplantation, the latest acquisitions in terms of genetic editing, as well as the improvement of immunosuppressive therapy are discussed analytically in this article in order to illustrate the underlying complexity of this therapeutic model.

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies.

BACKGROUND: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. OBJECTIVES: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. METHODS: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). RESULTS: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. CONCLUSIONS: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Reduced cardiac output (CO) has been considered crucial in symptoms' genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM. METHODS: CPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO <30; 10% between 30 and 49 and 18% ≥50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. RESULTS: We included 312 patients (70% males, age 49±18 years). Peak VO2 (percentage of predicted), O2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106±45 vs 130±49 W), VO2 (21.3±6.6 vs 24.1±7.7 mL/min/kg; 74%±17% vs 80%±20%) and O2-pulse (12 (9-14) vs 14 (11-17) mL/beat), with higher VE/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. CONCLUSION: None of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.

Prevalence and prognostic significance of ischemic late gadolinium enhancement pattern in non-ischemic dilated cardiomyopathy.

BACKGROUND: Typical late gadolinium enhancement (LGE) patterns in dilated cardiomyopathy (DCM) include intramyocardial and subepicardial distribution. However, the ischemic pattern of LGE (subendocardial and transmural) has also been reported in DCM without coronary artery disease (CAD), but its correlates and prognostic significance are still not known. On these bases, this study sought to describe the prevalence and prognostic significance of the ischemic LGE pattern in DCM. METHODS: A total of 611 DCM patients with available cardiac magnetic resonance were retrospectively analyzed. A composite of all-cause-death, major ventricular arrhythmias (MVAs), heart transplantation (HTx) or ventricular assist device (VAD) implantation was the primary outcome of the study. Secondary outcomes were a composite of sudden cardiac death or MVAs and a composite of death for refractory heart failure, HTx or VAD implantation. RESULTS: Ischemic LGE was found in 7% of DCM patients without significant CAD or history of myocardial infarction, most commonly inferior/inferolateral/anterolateral. Compared to patients with non-ischemic LGE, those with ischemic LGE had higher prevalence of hypertension and atrial fibrillation or flutter. Ischemic LGE was associated with worse long-term outcomes compared to non-ischemic LGE (36% vs 23% risk of primary outcome events at 5 years respectively, P = .006), and remained an independent predictor of primary outcome after adjustment for clinically and statistically significant variables (adjusted hazard ratio 2.059 [1.055-4.015], P = .034 with respect to non-ischemic LGE). CONCLUSIONS: The ischemic pattern of LGE is not uncommon among DCM patients without CAD and is independently associated with worse long-term outcomes.

Evidence of a double anaerobic threshold in healthy subjects.

AIMS: The anaerobic threshold (AT) is an important cardiopulmonary exercise test (CPET) parameter both in healthy and in patients. It is normally determined with three approaches: V-slope method, ventilatory equivalent method, and end-tidal method. The finding of different AT values with these methods is only anecdotic. We defined the presence of a double threshold (DT) when a ΔVO2 > 15 mL/min was observed between the V-slope method (met AT) and the other two methods (vent AT). The aim was to identify whether there is a DT in healthy subjects. METHODS AND RESULTS: We retrospectively analysed 476 healthy subjects who performed CPET in our laboratory between 2009 and 2018. We identified 51 subjects with a DT (11% of cases). Cardiopulmonary exercise test data at rest and during the exercise were not different in subjects with DT compared to those without. Met AT always preceded vent AT. Compared to subjects without DT, those with DT showed at met AT lower carbon dioxide output (VCO2), end-tidal carbon dioxide tension (PetCO2) and respiratory exchange ratio (RER), and higher ventilatory equivalent for carbon dioxide (VE/VCO2). Compared to met AT, vent AT showed a higher oxygen uptake (VO2), VCO2, ventilation, respiratory rate, RER, work rate, and PetCO2 but a lower VE/VCO2 and end-tidal oxygen tension. Finally, subjects with DT showed a higher VO2 increase during the isocapnic buffering period. CONCLUSION: Double threshold was present in healthy subjects. The presence of DT does not influence peak exercise performance, but it is associated with a delayed before acidosis-induced hyperventilation.

Prognostic significance of longitudinal strain in dilated cardiomyopathy with recovered ejection fraction.

OBJECTIVE: Patients with non-ischaemic dilated cardiomyopathy (NICM) may experience a normalisation in left ventricular ejection fraction (LVEF). Although this correlates with improved prognosis, it does not correspond to a normalisation in the risk of death during follow-up. Currently, there are no tools to risk stratify this population. We tested the hypothesis that absolute global longitudinal strain (aGLS) is associated with mortality in patients with NICM and recovered ejection fraction (LVEF). METHODS: We designed a retrospective, international, longitudinal cohort study enrolling patients with NICM with LVEF <40% improved to the normal range (>50%). We studied the relationship between aGLS measured at the time of the first recording of a normalised LVEF and all-cause mortality during follow-up. We considered aGLS >18% as normal and aGLS ≥16% as of potential prognostic value. RESULTS: 206 patients met inclusion criteria. Median age was 53.5 years (IQR 44.3-62.8) and 56.6% were males. LVEF at diagnosis was 32.0% (IQR 24.0-38.8). LVEF at the time of recovery was 55.0% (IQR 51.7-60.0). aGLS at the time of LVEF recovery was 13.6%±3.9%. 166 (80%) and 141 (68%) patients had aGLS ≤18% and <16%, respectively. During a follow-up of 5.5±2.8 years, 35 patients (17%) died. aGLS at the time of first recording of a recovered LVEF correlated with mortality during follow-up (HR 0.90, 95% CI 0.91 to 0.99, p=0.048 in adjusted Cox model). No deaths were observed in patients with normal aGLS (>18%). In unadjusted Kaplan-Meier survival analysis, aGLS <16% was associated with higher mortality during follow-up (31 deaths (22%) in patients with GLS <16% vs 4 deaths (6.2%) in patients with GLS ≥16%, HR 3.2, 95% CI 1.1 to 9, p=0.03). CONCLUSIONS: In patients with NICM and normalised LVEF, an impaired aGLS at the time of LVEF recovery is frequent and associated with worse outcomes.

The Arrhythmic Phenotype in Cardiomyopathy.

In the wide phenotypic spectrum of cardiomyopathies, sudden cardiac death (SCD) has always been the most visible and devastating disease complication. The introduction of implantable cardioverter-defibrillators for SCD prevention by the late 1980s has moved the question from how to whom we should protect from SCD, leaving clinicians with a measure of uncertainty regarding the most reliable option to guide identification of the highest-risk patients. In this review, we will go through all the available evidence in the field of arrhythmic expression and arrhythmic risk stratification in the different phenotypes of cardiomyopathies to provide practical suggestions in daily clinical management.

Prognostic Significance of Feature-Tracking Right Ventricular Global Longitudinal Strain in Non-ischemic Dilated Cardiomyopathy.

Aims: Left ventricular global longitudinal strain (GLS) by cardiac magnetic resonance feature tracking (CMR-FT) analysis has shown an incremental prognostic value compared to classical parameters in non-ischemic dilated cardiomyopathy (NICM). However, less is known about the role of right ventricular (RV) GLS. Our objective was to evaluate the prognostic impact of RV-GLS by CMR-FT analysis in a population of NICM patients. Methods: In this multicenter study, we examined NICM patients evaluated with a comprehensive CMR-FT study. Major cardiac events (MACEs) were considered as the study primary outcome measure and were defined as a composite of (a) cardiovascular death, (b) cardiac transplant or destination therapy ventricular assist device, (c) hospitalization for life-threatening ventricular arrhythmias or implantable cardiac defibrillator appropriate intervention. Heart failure (HF) related events, including hospitalizations and life-threatening arrhythmia-related events were considered as secondary end-points. Receiver operating time-dependent analysis were used to calculate the possible additional effect of RV-GLS to standard evaluation. Results: We consecutively enrolled 273 patients. During a median follow-up of 39 months, 41 patients (15%) experienced MACEs. RV-GLS and LV late gadolinium emerged as the strongest prognostic CMR-FT variables: their association provided an estimated 3-year MACEs rate of 29%. The addition of RV-GLS significantly improved the prognostic accuracy in predicting MACEs with respect to the standard evaluation including LGE (areas under the curve from 0.71 [0.66-0.82] to 0.76 [0.66-0.86], p = 0.03). On competing risk analysis, RV-GLS showed a significant ability to reclassify overall both HF-related and life-threatening arrhythmia-related events, regardless of LV and RV ejection fraction. Conclusions: In NICM patients, RV-GLS showed a significant prognostic role in reclassifying the risk of MACEs, incremental with respect to standard evaluation with standard prognostic parameters.

Prognostic role of global longitudinal strain by feature tracking in patients with hypertrophic cardiomyopathy: The STRAIN-HCM study.

BACKGROUND: The assessment of myocardial fiber deformation with cardiac magnetic resonance feature tracking (CMR-FT) has shown to be promising in terms of prognostic information in several structural heart diseases. However, little is known about its role in hypertrophic cardiomyopathy (HCM). Aims of the present study were: 1) to assess the prognostic role of CMR-FT derived strain parameters in patients with HCM. METHODS: CMR was performed in 130 consecutive HCM patients (93 males, mean age (54 ± 17 years) with an estimated 5-year risk of sudden cardiac death (SCD) <6% according to the HCM Risk-SCD calculator. 2D- and 3D-Global Radial (GRS), Longitudinal (GLS) and Circumferential (GCS) Strain was evaluated by FT analysis. The primary outcome of the study was a composite of major adverse cardiac events (MACE) including SCD, resuscitated cardiac arrest due to ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT), and hospitalization for heart failure. RESULTS: After a median follow-up of 51.7 (37.1-68.8) months, 4 (3%) patients died (all of them suffered from SCD) and 36 (28%) were hospitalized for heart failure. After multivariable adjustment for clinical and imaging covariates, among all strain parameters, only GLS remained a significant independent predictor of outcome events in both the model including 2D strain (HR 1.12, 95% CI 1.03-1.23, p = 0.01) and the model including 3D strain (HR 1.14, 95% CI 1.01-1.30, p = 0.04). The addition of 2D-GLS into the model with clinical and imaging predictors resulted in a significant increase in the C-statistic (from 0.48 to 0.65, p = 0.03). CONCLUSION: CMR-FT derived GLS is a powerful independent predictor of MACE in patients with HCM, incremental to common clinical and CMR risk factors including left ventricular ejection fraction and late gadolinium enhancement.

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

AIMS: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. METHODS AND RESULTS: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. CONCLUSION: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.

Roles of periodic breathing and isocapnic buffering period during exercise in heart failure.

In heart failure, exercise - induced periodic breathing and end tidal carbon dioxide pressure value during the isocapnic buffering period are two features identified at cardiopulmonary exercise testing strictly related to sympathetic activation. In the present review we analysed the physiology behind periodic breathing and the isocapnic buffering period and present the relevant prognostic value of both periodic breathing and the presence/absence of the identifiable isocapnic buffering period.

Management of nonischemic-dilated cardiomyopathies in clinical practice: a position paper of the working group on myocardial and pericardial diseases of Italian Society of Cardiology.

: Nonischemic-dilated cardiomyopathy (NIDCM) is an entity that gathers extremely heterogeneous diseases. This awareness, although leading to continuous improvement in survival, has increased the complexity of NIDCM patients' management. Even though the endorsed 'red-flags' approach helps clinicians in pursuing an accurate etiological definition in clinical practice, it is not clear when and how peripheral centers should interact with referral centers with specific expertise in challenging scenarios (e.g. postmyocarditis and genetically determined dilated cardiomyopathy) and with easier access to second-line diagnostic tools and therapies. This position paper will summarize each step in NIDCM management, highlighting the multiple interactions between peripheral and referral centers, from first-line diagnostic workup and therapy to advanced heart failure management and long-term follow-up.

Unpredictable Fall of Severe Emergent Cardiovascular Diseases Hospital Admissions During the COVID-19 Pandemic: Experience of a Single Large Center in Northern Italy.

Background Northern Italy is one of the epicenters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) pandemic in Europe. The impact of the pandemic and the consequent lockdown on medical emergencies other than those SARS-CoV 2 pandemic related is largely unknown. The aim of this study was to analyze the epidemiologic impact of coronavirus disease 2019 pandemic on hospital admission for severe emergent cardiovascular diseases (SECDs) in a single Northern Italy large tertiary referral center. Methods and Results We quantified SECDs admissions to the Cardiology Division of Udine University Hospital between March 1, 2020 and March 31, 2020 and compared them with those of the same time frame during 2019. Compared with March 2019, we observed a significant reduction in all SECDs admissions: -30% for ST-segment-elevation acute coronary syndromes, -66% for non-ST-segment-elevation acute coronary syndromes and -50% for severe bradyarrhythmia. Conclusions A significant decrease in all SECDs admissions has been observed during the SARS-CoV 2. pandemic and was unlikely caused by a reduction in the incidence of cardiovascular diseases. Fear of contagion may have contributed to the unpredictable drop of SECDs. Social education about early recognition of symptoms of life-threatening cardiac conditions requiring appropriate care in a timely fashion may help to reduce this counterproductive phenomenon.

Endomyocardial fibrosis of the right ventricle: A case report of successful surgery.

AIMS: The case we report, shows a successful treatment of right ventricle endomyocardial fibrosis. MATERIALS AND METHODS: Surgical therapy by endocardial decortication seems to be beneficial for many patients with advanced disease who are in functional-therapeutic class III or IV. The operative mortality rate is high, but successful surgery has a clear benefit on symptoms and seems to favourably affect survival as well.

Treatment of Functional Mitral Regurgitation in Heart Failure.

PURPOSE OF REVIEW: To analyze the current state of the art of functional mitral regurgitation (FMR) treatment. RECENT FINDINGS: The first-line treatment of severe FMR consists of guideline medical therapy (GMT) and resynchronization therapy when indicated; the impact of new medical therapies like sacubitril/valsartan needs further assessment. Valvular intervention may be considered in FMR symptomatic patients despite GMT, and can be performed surgically or percutaneously. MitraClip is a safe percutaneous procedure associated with symptoms improvement. Recently, the COAPT trial showed superior outcomes for MitraClip versus GMT contrasting the MITRA-FR trial which showed no benefit of MitraClip compared with GMT. These results should be interpreted as complementary rather than opposite. The COAPT trial provided a "proof of concept" that percutaneous treatment of severe FMR in patients without too advanced left ventricular disease translates into a prognostic benefit. Careful patient selection will play a critical role in defining the clinical niche for successful interventions.

Usefulness of Addition of Magnetic Resonance Imaging to Echocardiographic Imaging to Predict Left Ventricular Reverse Remodeling in Patients With Nonischemic Cardiomyopathy.

Defining short-term prognosis in nonischemic cardiomyopathy (NICM) is challenging in clinical practice. Although left ventricular reverse remodeling (LVRR) is a key prognostic marker in NICM there are few parameters able to predict it. We investigated whether a complete structural and functional cardiac magnetic resonance imaging (cMRI) evaluation was incremental to the classic clinical-echocardiographic approach in predicting LVRR in a large cohort of NICM patients receiving evidence-based treatment. Patients with a recent diagnosis of NICM (<3 months) who underwent complete clinical, echocardiographic and cMRI assessment were consecutively enrolled from 2008 to 2016. LVRR was defined as an increase in ≥10 points or normalization of left ventricular ejection fraction, associated with a ≥10% reduction or normalization of left ventricular end-diastolic diameter at midterm (median time 20 months) echocardiographic follow-up. Among 80 NICM patients included in the study, LVRR was observed in 43 (54%). At multivariate analysis, the clinical-echocardiographic evaluation failed to identify independent predictors of LVRR. However, absence of late gadolinium enhancement (odds ratio [OR] 9.07; confidence interval [CI] 2.7 to 13.1; p value 0.0003), left ventricular mass (OR 1.018; CI 1.001 to 1.036; p value 0.045) and peak circumferential strain (OR 1.213; CI 1.011 to 1.470; p value 0.049) assessed by cMRI were independently associated with LVRR. A model for LVRR prediction based on cMRI and clinical-echocardiographic parameters performed significantly better than the clinical-echocardiographic model alone (area under curve 0.84 vs 0.72; p value 0.023). In conclusion, an integrated imaging approach with the addition of a structural and functional cMRI study to the standard-of-care evaluation improves the prediction of LVRR in a large cohort of patients with recently diagnosed NICM receiving evidence-based treatment.

Arrhythmic Risk Stratification in Patients With Idiopathic Dilated Cardiomyopathy.

Arrhythmic risk stratification in idiopathic dilated cardiomyopathy (IDC) remains a major concern. As the ventricles remodel in time, risk factors for arrhythmic death may change. A cohort of 710 patients with idiopathic dilated cardiomyopathy, without previous ventricular arrhythmias, was retrospectively studied to understand how risks vary in time. The primary end point was a composite of sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator interventions. The prediction of the arrhythmic outcome was assessed dynamically through landmark analysis. Patients were assessed at baseline, short term (12 months, interquartile range 6 to 18), and long-term (72 months, interquartile range 60 to 84). The strongest risk predictors at each evaluation were combined in 3 multivariate models. During a median follow-up of 102 months, 80 patients (11%) experienced the primary end point. At baseline, QRS duration (p = 0.008), disease duration (p <0.001), and mitral regurgitation (p = 0.010) were significantly associated with the primary end point. The 12 months' landmark model included disease duration (p = 0.049), syncope (p = 0.005), New York Heart Association classes III and IV (p = 0.02), and indexed left ventricular end-diastolic volume (p = 0.001). Finally, the 72 months' landmark model combined the indexed left ventricular end-diastolic volume (p = 0.048), the left ventricular ejection fraction (p = 0.008), and the left atrial area (p = 0.001). All the 3 models provided a satisfactory accuracy (area under the curve ranging from 0.76 to 0.82, p <0.001). With an implantable cardioverter-defibrillator, the natural course of the disease influences the effect of arrhythmic risk factors overtime. Different predictors should be considered for the risk stratification according to the timing of assessment. Impaired left ventricular ejection fraction was significantly associated with major arrhythmias only in the long term.