Prognostic implications of nonsustained ventricular tachycardia morphology in high-risk patients with hypertrophic cardiomyopathy.

INTRODUCTION: The prognostic impact of nonsustained ventricular tachycardia (NSVT) morphology has never been explored in hypertrophic cardiomyopathy (HCM). In a single-center cohort of consecutive HCM patients implanted with an implanted cardioverter-defibrillator (ICD), we assessed NSVT morphology patterns and their prognostic implications. METHODS: A cohort of consecutive HCM patients implanted with an ICD was followed from ICD implantation to last follow-up visit. Patients were assessed for NSVT as stored events in ICD memory. Ventricular tachycardias (VTs) were classified as monomorphic (MM) or polymorphic according to intracardiac electrogram morphology. RESULTS: One hundred nine consecutive HCM patients (68 males; mean age: 45 ± 17 years) composed the study population. During follow-up (71 ± 48 months), 7 polymorphic NSVT in 4 patients and 370 MM NSVT in 42 patients were retrieved from ICD memory. Among patients with only MM NSVT, 19 (45%) had one morphology, 17 (41%) had two morphologies, 3 (7%) had three morphologies, and 3 (7%) had four morphologies. Patients with polymorphic NSVT had the highest risk of ICD interventions (HR, 5.04; 95% CI, 1.26-20.19; P = .02). A stepwise increase of the risk of ICD interventions in patients with two, three, and four NSVT morphologies was observed. Out of 16 patients with both NSVT and ICD-treated VTs, 13 (81%) had at least one ICD-treated VT with the same morphology of a previous long-lasting NSVT. CONCLUSIONS: In high-risk HCM patients, the occurrence of polymorphic NSVT and of NSVT with multiple morphologies carries a high risk for ICD interventions. Sustained VTs tend to recur with the same morphology of previous long-lasting NSVTs.

Safety and efficacy of anti-tachycardia pacing in patients with hypertrophic cardiomyopathy implanted with an ICD.

BACKGROUND: In hypertrophic cardiomyopathy (HCM) patients implanted with an implantable cardioverter defibrillator (ICD), clinical outcomes of antitachycardia pacing (ATP) have been poorly explored. In a retrospective analysis of a cohort of consecutive HCM patients implanted with an ICD, we aimed to assess the efficacy, safety, and clinical value of ATP. METHODS: The cohort of HCM patients implanted with a transvenous ICD and followed in our center was assessed for device intervention from implantation to last clinical follow-up. RESULTS: Overall 77 patients (45 males; mean age: 46 ± 16 years) were analyzed. After 67 ± 41 months, 24 patients had 49 ventricular tachycardia/fibrillation (VT/VF) appropriately treated (5.8% per year). Among 39 monomorphic VTs, ATP was effective in 27 (success rate: 69%). Mean time from VT onset to ATP delivery was 9.1 ± 4.9 s. The only clinical variable improving ATP success was use of beta-blockers (81% vs 50%; P = .04). Out of 12 ineffectively treated VTs, one was immediately shocked, four self-terminated after 18 ± 12 s, and seven (18%) were accelerated to a new VT. ATP was also delivered for 27 of 42 inappropriately detected episodes and induced two de novo VTs (7%). In the per patient analysis, 14 out 77 (18%) patients had one or more appropriate and effective ATP (3.4% per year), and only six (8%; 1.4% per year) received more than one ATP. CONCLUSION: ATP is moderately effective for the treatment of monomorphic VTs in HCM patients. However, the rate of appropriate ATP therapies is low, ATP is often prematurely delivered, and ATP-induced arrhythmia degeneration is of concern.

Prognostic Implications of Defibrillation Threshold Testing in Patients With Hypertrophic Cardiomyopathy.

INTRODUCTION: In hypertrophic cardiomyopathy (HCM) patients the need for defibrillation threshold (DFT) testing at the time of ICD implantation is debated. Moreover, its prognostic implications have never been explored. In a cohort of HCM patients we sought to (a) investigate factors prompting DFT testing, (b) evaluate ICD efficacy by testing DFT, (c) compare DFT in patients with and without massive LVH, and (d) assess whether DFT testing predicts shock efficacy for spontaneous VT/VF. METHODS AND RESULTS: We retrospectively analyzed a cohort of HCM patients implanted with an ICD. DFT was tested at the discretion of the implanting physician with a 10 J safety margin. During follow-up, ICD interventions were evaluated. The study population included 66 patients. DFT was determined in 25 (38%) patients. Age (HR: 0.95; 95%CI: 0.92-0.98; P = 0.004) and massive LVH (HR: 6.0; 95%CI: 2.03-18.8; P = 0.001) affected the decision to test DFT. DFT was at least 10 J less than maximal ICD output in 25/25. Safety margin was similar among patients with and without massive LVH (15 ± 3 J vs. 14 ± 2 J; P = 0.42). During follow-up (median 53 months) 15 shocks were delivered for 12 VT/VF in 7 patients. One VF ended spontaneously after a failed shock. Of 4 unsuccessful shocks, 2 occurred in 1 patient with DFT testing and 2 were delivered in 2 patients without. All unsuccessful shocks were ≤35 J. CONCLUSION: Young age and massive LVH prompt DFT testing. Contemporary ICDs are safe and effective in HCM patients independently from the magnitude of LVH. DFT testing does not predict shock efficacy for spontaneous VT/VF.

Eligibility for the Subcutaneous Implantable Cardioverter-Defibrillator in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: High-risk hypertrophic cardiomyopathy (HCM) patients benefit from the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) may provide comparable protection while avoiding the shortcomings of transvenous (TV) leads. We assessed S-ICD eligibility according to surface ECG screening test in a cohort of high-risk HCM patients. METHODS AND RESULTS: 47 HCM patients (3 S-ICD candidates; 41 TV-ICD patients without pacing indication; and 3 pacemaker-dependent TV-ICD patients) underwent 4 screening protocols: standard (n = 44); exercise (n = 33); continuous pacing (n = 44); alternating paced/spontaneous QRS (n = 41). Of the 44 patients in the standard screening group, 41 (93%) were eligible. Max LV thickness was inversely related to the number of qualifying leads (3 leads: 21 ± 4 mm; 2 leads: 22 ± 6 mm; 1 lead: 25 ± 6 mm; no leads: 28 ± 11 mm; P = 0.07). Of the 33 patients in the exercise group, 5 were ineligible (3 after exercise). Of these, 2 became eligible after moving sternal electrodes from the left to the right parasternal line (eligibility rate: 30/33; 91%). Of the 44 patients in the continuous pacing group, 28 (64%) were eligible, 8 of which with right parasternal electrodes. In the paced/spontaneous QRS group (n = 41), 21 patients (51%) had at least 1 eligible lead during pacing and retained compatibility on the same lead during spontaneous rhythm, 5 of which with right parasternal electrodes. CONCLUSIONS: S-ICD screening failure is low in HCM, provided that patients with severe hypertrophy are carefully evaluated. Exercise test should be performed and right parasternal leads tested. Pacemaker patients display lower eligibility rate.

RyR2 Common Gene Variant G1886S and the Risk of Ventricular Arrhythmias in ICD Patients with Heart Failure.

BACKGROUND: Cardiac ryanodine receptor 2 (RyR2) is critical to the electrical homeostasis of cardiomyocytes. Its gene variant rs3766871 entails channel destabilization and enhanced intracellular Ca(2+) oscillation, thus promoting cardiac arrhythmias. We investigated whether the RyR2 rs3766871 variant is associated with aborted sudden cardiac death or ICD therapy for ventricular tachycardia (VT)/fibrillation (VF) in heart failure (HF) patients implanted with a cardioverter defibrillator (ICD). METHODS AND RESULTS: A total of 183 HF patients with primary or secondary prevention ICD were divided in 2 groups. A VT/VF group was composed of secondary prevention patients and primary prevention patients with appropriate ICD intervention for VT/VF. An ICD control group was composed of primary prevention patients free from any appropriate ICD intervention after 43 ± 25 months follow-up. Study subjects were genotyped with respect to the rs3766871 RyR2 gene variant. Hazard ratios (HRs) were derived from Cox proportional-hazards regression analysis. In all, 56 patients constituted the VT/VF group and 127 patients the ICD control group. Male sex (HR: 3.02; 95% CI: 0.99-9.18; P = 0.05), atrial fibrillation (AF; HR: 2.33; 95% CI: 0.89-6.10; P = 0.08), and underuse of ß-blockers (HR: 2.08; 95% CI: 0.84-5.15; P = 0.11) were associated with the VT/VF phenotype. Prevalence of the rs3766871 minor allele was 2.8% in ICD control patients and 8.0% in the VT/VF group (P = 0.02). After adjustment for age, sex, AF, and use of ß-blockers, the rs3766871 minor allele was associated with increased risk of VT/VF (HR: 3.49; 95% CI: 1.14-10.62; P = 0.02). CONCLUSIONS: Our study identifies a significant role of RyR2 rs3766871 minor allele for increased susceptibility to VT/VF in a population of ICD patients with HF.

Antihypertensive therapy in diabetes: the legacy effect and RAAS blockade.

Two recently published post-monitoring follow-up studies of the United Kingdom Prospective Diabetes Study (UKPDS) have shown that although early and intensive treatment of hyperglycemia provides benefits for cardiovascular mortality that extend over time, the effects of a tight antihypertensive strategy in patients with diabetes did not seem to last during the following years. The authors concluded that blood pressure control is of crucial importance in patients with diabetes but is not protective against cardiovascular events when it is not sustained. Several lines of evidence suggest, however, that early and intensive antihypertensive treatment with some classes of drugs exerts benefits that may persist during the following years. Particularly, blockade of the renin-angiotensin-aldosterone system (RAAS) may interrupt the molecular and cellular mechanisms underlying cardiac and vascular remodeling and the maintenance of high blood pressure values. This review article critically discusses current evidence and explores the rationale for a legacy effect of RAAS blockade in hypertensive patients with diabetes.

[The progression from hypertension to congestive heart failure]. / Attuali concetti sullo sviluppo dell'insufficienza cardiaca nell'ipertensione.

Arterial hypertension still represents one of the major modifiable risk factors for cardiovascular and renal disease. Solid evidences are available demonstrating the large and significant benefits deriving from blood pressure lowering therapies in terms of reduced incidence of major cardiovascular events, including myocardial infarction, ischemic stroke and cardiovascular death. It should be also noted, however, that hypertensive patients are at increased risk of developing congestive heart failure, being this risk substantially independent by the concomitant presence of left ventricular hypertrophy or dysfunction. Indeed, it has been demonstrated that blood pressure reduction and control significantly reduce the risk of developing congestive heart failure. In particular, several recent meta-analyses have demonstrated that the use of diuretics and renin-angiotensin system blockers is superior to calcium-antagonists and beta-blockers in terms of prevention of new-onset heart failure. The present paper overviews the main pathophysiological aspects of the progression from arterial hypertension to congestive heart failure and the potential therapeutic interventions able to reduce or prevent this progression.

Left Ventricular Remodeling in Hypertrophic Cardiomyopathy: An Overview of Current Knowledge.

While most patients with hypertrophic cardiomyopathy (HCM) show a relatively stable morphologic and clinical phenotype, in some others, progressive changes in the left ventricular (LV) wall thickness, cavity size, and function, defined, overall, as "LV remodeling", may occur. The interplay of multiple pathophysiologic mechanisms, from genetic background to myocardial ischemia and fibrosis, is implicated in this process. Different patterns of LV remodeling have been recognized and are associated with a specific impact on the clinical course and management of the disease. These findings underline the need for and the importance of serial multimodal clinical and instrumental evaluations to identify and further characterize the LV remodeling phenomenon. A more complete definition of the stages of the disease may present a chance to improve the management of HCM patients.

Novel Imaging and Genetic Risk Markers in Takotsubo Syndrome.

Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening.

Prevention of Sudden Cardiac Death: Focus on the Subcutaneous Implantable Cardioverter-Defibrillator.

The implantable cardioverter-defibrillator (ICD) is the most effective therapy to prevent sudden cardiac death (SCD) in high-risk patients. To overcome infections and failure of transvenous leads, the most frightening complications of conventional ICDs, a completely subcutaneous ICD (S-ICD) has been developed and is currently adopted in routine clinical practice. In view of their long life-expectancy, low competitive risk of dying from non-arrhythmic causes, and high lifetime risk of lead-related complications requiring surgical revisions, young patients with cardiomyopathies and inherited arrhythmia syndromes have traditionally been considered ideal candidates for the S-ICD. However, as growing evidence supported S-ICD safety and efficacy, initial niche implant indications were abandoned in favor of a widespread use of this technology, that is currently adopted in common ICD candidates with severe left ventricular dysfunction. Indeed, guidelines recommend S-ICD implantation as an alternative to TV-ICDs in all ICD candidates, unless pacing is required. This review focuses on the contemporary experience with the S-ICD and explores future scenarios in which device-to-device communication will enable to combine leadless therapies.

Assessing Atrial Fibrillation Substrates by P Wave Analysis: A Comprehensive Review.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pharmacologic and non-pharmacologic rhythm control strategies impact on AF-related symptoms, while leaving largely unaffected the risk of stroke. Moreover, up to 20% of AF patients are asymptomatic during paroxysmal relapses of arrhythmia, thus underlying the need for early markers to identify at-risk patients and prevent cerebrovascular accidents. Indeed, non-invasive assessment of pre-clinical substrate changes that predispose to AF could provide early identification of at-risk patients and allow for tailored care paths. ECG-derived P wave analysis is a simple-to-use and inexpensive tool that has been successfully employed to detect AF-associated structural and functional atrial changes. Beyond standard electrocardiographic techniques, high resolution signal averaged electrocardiography (SAECG), by recording microvolt amplitude atrial signals, allows more accurate analysis of the P wave and possibly AF risk stratification. This review focuses on the evidence that support P wave analysis to assess AF substrates, predict arrhythmia relapses and guide rhythm-control interventions.

Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction.

Left ventricular diastolic dysfunction represents a frequent clinical condition and is associated with increased cardiovascular morbidity and mortality. Diastolic dysfunction is the most common cause of HF-PSF (heart failure with preserved ejection fraction). Therefore it becomes important to understand the pathophysiological mechanisms underlying diastolic dysfunction, as well as the effective therapeutic strategies able to antagonize its development and progression. Among the complex pathophysiological factors that may contribute to the development of diastolic dysfunction, the RAAS (renin-angiotensin-aldosterone system) has been shown to play a significant role. Paracrine and autocrine signals of the RAAS promote structural and functional changes in the heart largely linked to increased myocardial fibrosis. Enhanced and dysregulated activity of the RAAS also contributes to the development of volume overload and vasoconstriction with subsequent increases in left ventricular diastolic filling pressures and a higher susceptibility of developing CHF (congestive heart failure). More recently, it has also been suggested that the RAAS may play a role in triggering myocardial and vascular inflammation through the activation of different cell types and the secretion of cytokines and chemokines. RAAS-induced myocardial inflammation leads to perivascular myocardial fibrosis and to the development or progression of diastolic dysfunction. For these reasons pharmacological blockade of the RAAS has been proposed as a rational approach for the treatment of diastolic dysfunction. In fact, ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor blockers) and AAs (aldosterone antagonists) have been demonstrated to delay the development and progression from pre-clinical diastolic dysfunction towards CHF, as well as to reduce the morbidity and mortality associated with this condition.

The subcutaneous implantable cardioverter-defibrillator: Current trends in clinical practice between guidelines and technology progress.

The subcutaneous implantable cardioverter defibrillator (S-ICD) is a valuable alternative to the conventional trans-venous ICD (TV-ICD) for the prevention of sudden cardiac death (SCD). Prospective registries showed that the S-ICD is safe and effective in treating ventricular tachyarrhythmias in high-risk patients without pacing indications. While in earlier studies patients implanted with S-ICDs were young and mostly affected by channelopathies, contemporary S-ICD cohorts include patients with severely impaired left ventricular function and significant comorbidities. This review focuses on S-ICD evidence-based use and highlights current gaps between guidelines recommendations and real-world clinical practice.

Safety, Efficacy and Evidence Base for Use of the Subcutaneous Implantable Cardioverter Defibrillator.

The trans-venous implantable cardioverter defibrillator (TV-ICD) is effective in treating life-threatening ventricular arrhythmia and reduces mortality in high-risk patients. However, there are significant short- and long-term complications that are associated with intravascular leads. These shortcomings are mostly relevant in young patients with long life expectancy and low risk of death from non-arrhythmic causes. Drawbacks of trans-venous leads recently led to the development of the entirely subcutaneous implantable cardioverter defibrillator (S-ICD). The S-ICD does not require vascular access or permanent intravascular defibrillation leads. Therefore, it is expected to overcome many complications associated with conventional ICDs. This review highlights data on safety and efficacy of the S-ICD and is envisioned to help in identifying the role of this device in clinical practice.

Autonomic cardiovascular control and cardiac arrhythmia in two pregnant women with hypertrophic cardiomyopathy: Insights from ICD monitoring.

In women with hypertrophic cardiomyopathy (HCM), pregnancy prompts major changes in hemodynamic and cardiac autonomic function that may precipitate heart failure (HF) or increase the risk of cardiac arrhythmia. We report the clinical follow-up of two patients with non-obstructive HCM implanted with a cardioverter defibrillator (ICD) allowing for continuous analysis of heart rate (HR), heart rate variability (HRV) and cardiac arrhythmia throughout the entire course of pregnancy. Both patients experienced increased HR and decreased HRV from the early stages of pregnancy, which persisted until delivery. Premature ventricular contractions (PVCs) and runs of non-sustained ventricular tachycardia (NSVT) reached a peak in the second and third trimesters, concurrent with sympathetic hyperactivity. In one patient with baseline NYHA class II HF symptoms, increased PVCs and NSVT were consistent with the deterioration of HF, supporting the decision to bring the delivery forward. While both patients experienced a persistent increase in sympathetic tone and ventricular ectopic activity, no life-threatening arrhythmias were documented. During pregnancy, patients with hypertrophic cardiomyopathy develop progressive neuroautonomic imbalance, prompting an increase in non-sustained ventricular arrhythmia. This enhanced arrhythmia burden warrants close follow-up and rhythm assessment during the third trimester, especially in women who have heart failure symptoms before pregnancy. Implantable cardioverter defibrillators provide a continuous analysis of heart rate variability and arrhythmia burden that supports therapeutic decision-making during follow-up.

Subcutaneous implantable cardioverter defibrillator eligibility according to a novel automated screening tool and agreement with the standard manual electrocardiographic morphology tool.

PURPOSE: Since subcutaneous implantable cardioverter defibrillator (S-ICD) introduction, the pre-implant screening based on a dedicated manual ECG tool (MST) was required to assure adequate sensing by the S-ICD. A novel automated screening tool (AST) has been recently developed. We assessed and compared the pass rate with AST and MST, and we measured the agreement between screening tools. METHODS: Three electrodes were positioned at locations mimicking the placement of the S-ICD, and ECG recordings were collected in the supine and standing postures at rest. The three sensing vectors were analyzed with the MST and the AST. Eligibility was defined by the presence of at least one or two appropriate vectors in both postures. RESULTS: A total of 235 patients with an indication to ICD and no need for permanent pacing were enrolled. At least one suitable vector was identified in 214 (91%) patients with MST and 221 (94%) patients with AST (p = 0.219). At least two vectors were appropriate in 162 (69%) patients with MST and 187 (80%) patients with AST (p = 0.008). Overall, out of 1587 ECG analyzed, 1035 (65%) qualifying leads were identified with MST and 1111 (70%) with AST (p = 0.004). The agreement between the results of MST and AST ECG analysis was moderate (Kappa = 0.570; standard error = 0.022; CI = 0.526-0.613). The results were consistent regardless of the underlying cardiomyopathy. The most frequent reason for screening failure with MST was a high-amplitude T-wave (31% of failures). With AST, 23% of recordings that failed with MST for high-amplitude T-wave were classified as acceptable. CONCLUSION: The AST is associated with higher pass rate than the standard MST. It seems more tolerant of high-amplitude T-waves. Consequently, the agreement between MST and AST findings was only moderate.

A Novel Electrocardiographic T-Wave Measurement (Tp-Te Interval) as a Predictor of Heart Abnormalities in Hypertension: A New Opportunity for First-Line Electrocardiographic Evaluation.

The aim of the study was to evaluate the role of conventional and new markers of early cardiac organ damage (OD) on 12-lead electrocardiography (ECG) in 25 outpatients with newly diagnosed untreated essential hypertension compared with 15 normotensive, otherwise healthy individuals. Each participant underwent ECG, echocardiographic, and blood pressure (BP) measurements. Conventional and new ECG indexes for cardiac OD (Tp-Te interval, ventricular activation time, and P-wave analysis) were also measured. Clinic and 24-hour ambulatory BP levels as well as left ventricular mass indexes were significantly higher in hypertensive than in normotensive patients. No significant differences were found between the two groups for ECG and echocardiographic markers of OD. Only Tp-Te interval was higher in hypertensive than in normotensive individuals (3.06 mm vs 2.24 mm; P<.0001), even after adjustment for anthropometric and clinical parameters. Preliminary results of this study demonstrated prolonged Tp-Te interval in newly diagnosed, untreated hypertensive outpatients compared with normotensive individuals.

Impact of hypertension on global cardiovascular risk stratification: analysis of a large cohort of outpatient population in Italy.

BACKGROUND: Control of hypertension remains a major unmet need, worldwide. HYPOTHESIS: To test whether the presence of hypertension may improve global cardiovascular (CV) risk stratification and achievement of therapeutic targets for CV risk factors in adult outpatients in Italy. METHODS: Physicians were asked to submit data covering the first 10 consecutive adult outpatients. All data were centrally analyzed for global CV risk assessment and rates of control of major CV risk factors, mostly blood pressure (BP) levels, in different high-risk subgroups of hypertensive patients. RESULTS: Overall, 1078 physicians collected data of 9864 outpatients (46.7% females, age 66.1 ± 10.3 years) with valuable data on BP levels, among which 7147 (72.5%) had a diagnosis of hypertension and 2717 (27.5%) were normotensive subjects. Hypertensive patients were older and had a higher prevalence of major risk factors, including smoking, obesity, dyslipidemia, and family history of cardiovascular disease, as well as comorbidities, than did normotensive subjects (P < 0.001 for all comparisons). Despite worse control of BP (66.9% vs 36.2%, P < 0.001), high-density lipoprotein cholesterol (40.5% vs 37.4%, P < 0.005), triglycerides (72.1% vs 67.8%, P < 0.001), and fasting plasma glucose (71.2% vs 67.0%, P < 0.005), hypertension was associated with larger availability and frequency of diagnostic examinations and greater use of antihypertensive, glucose-lowering, and lipid-lowering drugs, as well as antiplatelet agents, compared with normotension (P < 0.001). CONCLUSIONS: Presence of hypertension significantly improved clinical data collection and CV risk stratification. Such an approach, however, was not paralleled by better control of major CV risk factors.

Angiotensin receptor antagonists to prevent sudden death in heart failure: does the dose matter?

International guidelines recommend ICD implantation in patients with severe left ventricular dysfunction of any origin only after careful optimization of medical therapy. Indeed, major randomized clinical trials suggest that suboptimal use of fundamental drugs, such as ACE inhibitors (ACE-i) and beta-blockers, may affect ICD shock-free survival, sudden cardiac death (SCD), and overall mortality. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with angiotensin receptor blockers (ARBs) are limited. The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of arrhythmic substrates. The following hypothesis is supported: (1) the RAS is a critical component of the electrical remodelling of the failing myocardium, (2) RAS blockade reduces the risk of SCD, and (3) ARBs represent a powerful tool to improve overall survival and possibly reduce the risk of SCD provided that high doses are employed to achieve optimal AT1-receptor blockade.