Long QT syndrome: importance of reassessing arrhythmic risk after treatment initiation.

BACKGROUND AND AIMS: Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate. METHODS: LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years. RESULTS: Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (ßB) therapy in 94% of them reduced the rate of those with a QTc ≥500 ms from 18% to 12% (P < .001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received ßBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had CEs. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3. CONCLUSIONS: Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events.

Implantable loop recorders in patients with Brugada syndrome: the BruLoop study.

BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.

Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping for KCNH2-LQTS Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data. Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,323 variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort. Results: Variant-specific current density (HR 0.28 [0.13-0.60]) and estimates of LQTS penetrance incorporating MAVE data (HR 3.16 [1.59-6.27]) were independently predictive of severe cardiac events when controlling for patient-specific features. Risk prediction models incorporating these data significantly improved prediction of 20 year cardiac events (AUC 0.79 [0.75-0.82]) over patient-only covariates (QTc and sex) (AUC 0.73 [0.70-0.77]). Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease.

ECG/echo indexes in the diagnostic approach to amyloid cardiomyopathy: A head-to-head comparison from the AC-TIVE study.

BACKGROUND AND AIMS: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients. METHODS: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed. RESULTS: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007). CONCLUSIONS: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted.

Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

Clinical Management of Brugada Syndrome: Commentary From the Experts.

Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Executive Attentional Dyscontrol as a Core Cognitive and Behavioral Feature of Individuals with Obesity and Cardiovascular Disease: A Cross-Sectional Investigation.

Executive attention as a frontal domain ability that is effective in potentially blocking distracting information, reconciling conflicts among simultaneous attentional demands, and regulating impulsive behavior may be impaired in individuals with obesity and cardiovascular disease (CVD). This study aimed (i) to explore the presence of selected cognitive (global cognitive impairment, sensitivity to interference, and attention) and psychological (quality of life, depression, anxiety, and impulsivity) dimensions and (ii) to examine the interactive relationship between attentional dyscontrol-both as a psychological and as a cognitive measure-and the above-mentioned variables in a sample of patients with CVD attending a cardiac rehabilitation program across different body mass index (BMI) levels. Clinical information of 104 patients with CVD was retrospectively collected. Participants were classified into three groups according to their BMI as follows: normal weight (NW = 30), overweight (OW = 19), and obese (OB = 55). Individuals with CVD and a higher BMI showed problems in controlling executive attention-through both neuropsychological and behavioral measures. Specifically, OB patients demonstrated reduced sensitivity to cognitive interference, lower capabilities in divided attention during visual-tracking tasks, and greater impulsivity compared to NW patients. This behavioral characteristic was also found to be correlated with higher levels of anxiety and depression and a lower quality of life. Implications for cognitive rehabilitation were discussed to offer directions for better management of patients with CVD and obesity.

From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies.

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families.

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

The Lancet Commission to reduce the global burden of sudden cardiac death: a call for multidisciplinary action.

Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.

Current gaps in knowledge in inherited arrhythmia syndromes.

The 3 most common inherited arrhythmia syndromes-Brugada syndrome, congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-were initially described in the previous century. Since then, research has evolved, which has enabled us to identify patients prior to the onset of potentially life-threatening symptoms. However, there are significant gaps in knowledge that complicate clinical management of these patients today. With this review paper, we aim to highlight the most important knowledge gaps in clinical research of these inherited arrhythmia syndromes.

From the phenotype to precision medicine: an update on the cardiomyopathies diagnostic workflow.

Cardiomyopathies are disease of the cardiac muscle largely due to genetic alterations of proteins with 'structural' or 'functional' roles within the cardiomyocyte, going from the regulation of contraction-relaxation, metabolic and energetic processes to ionic fluxes. Modifications occurring to these proteins are responsible, in the vast majority of cases, for the phenotypic manifestations of the disease, including hypertrophic, dilated, arrhythmogenic and restrictive cardiomyopathies. Secondary nonhereditary causes to be excluded include infections, toxicity from drugs or alcohol or medications, hormonal imbalance and so on. Obtaining a phenotypic definition and an etiological diagnosis is becoming increasingly relevant and feasible, thanks to the availability of new tailored treatments and the diagnostic advancements made particularly in the field of genetics. This is, for example, the case for transthyretin cardiac amyloidosis, Fabry disease or dilated cardiomyopathies due to laminopathies. For these diseases, specific medications have been developed, and a more tailored arrhythmic risk stratification guides the implantation of a defibrillator. In addition, new medications directly targeting the altered protein responsible for the phenotype are becoming available (including the myosin inhibitors mavacantem and aficamten, monoclonal antibodies against Ras-MAPK, genetic therapies for sarcoglycanopathies), thus making a precision medicine approach less unrealistic even in the field of cardiomyopathies. For these reasons, a contemporary approach to cardiomyopathies must consider diagnostic algorithms founded on the clinical suspicion of the disease and developed towards a more precise phenotypic definition and etiological diagnosis, based on a multidisciplinary methodology putting together specialists from different disciplines, facilities for advanced imaging testing and genetic and anatomopathological competencies.

Diagnostic and prognostic electrocardiographic features in patients with hypertrophic cardiomyopathy.

The standard 12-lead electrocardiogram (ECG) represents a cornerstone for the diagnosis and evaluation of hypertrophic cardiomyopathy (HCM), the most common genetically determined heart muscle disease, due to its cost-effectiveness and wide availability. The ECG may surprisingly look normal in 4-6% of adult patients, and in less than 3% of paediatric patients, but it is abnormal in the vast majority of the remaining patients. 'Specific' features comprise pathological Q-waves, deep S-waves in V1-V3, or high R-waves in V4-V6 due to left ventricular hypertrophy with T-wave (TW) depression or negative TWs. Negative giant TWs are often found in apical HCM. However, in many patients, the ECG may only show non-specific ST-T changes with diphasic or flat TWs. An isolated inverted TW in lateral leads (usually aVL) may be the only marker for HCM in some patients. Electrocardiogram helps to diagnose sarcomeric HCM and distinguish it from different phenocopies, such as cardiac amyloidosis, glycogen storage, or Fabry disease. Electrocardiogram may also have a prognostic role, identifying high-risk features that could impact the clinical outcome.

Genetic Testing and Counselling in Hypertrophic Cardiomyopathy: Frequently Asked Questions.

Genetic counselling and genetic testing in hypertrophic cardiomyopathy (HCM) represent an integral part of the diagnostic algorithm to confirm the diagnosis, distinguish it from phenocopies, and suggest tailored therapeutic intervention strategies. Additionally, they enable cascade genetic testing in the family. With the implementation of Next Generation Sequencing technologies (NGS), the interpretation of genetic data has become more complex. In this regard, cardiologists play a central role, aiding geneticists to correctly evaluate the pathogenicity of the identified genetic alterations. In the ideal setting, geneticists and cardiologists must work side by side to diagnose HCM as well as convey the correct information to patients in response to their many questions and concerns. After a brief overview of the role of genetics in the diagnosis of HCM, we present and discuss the frequently asked questions by HCM patients throughout our 20-year genetic counselling experience. Appropriate communication between the team and the families is key to the goal of delivering the full potential of genetic testing to our patients.

Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

AIMS: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM. CONCLUSION: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

Effects of cardiac rehabilitation on cardiopulmonary test parameters in heart failure: A real world experience.

Background: Cardio-Pulmonary Exercise Test (CPET) is the gold standard for evaluation of patients with heart failure (HF); however, its use is limited in everyday practice. We analyzed the use of CPET for HF management in the real world. Methods: From 2009 to 2022, 341 patients with HF underwent 12-16 weeks of rehabilitation in our Centre. We present data from 203 patients (60%), excluding those unable to perform CPET, those with anaemia and severe pulmonary disease. Before and after rehabilitation, we performed CPET, blood tests and echocardiography, tailoring individual physical training to the results of baseline test. The following variables were considered: peak Respiratory Equivalent Ratio (RER), peakVO2 (ml/Kg/min), VO2 at aerobic threshold (VO2AT,% maximal), VE/VCO2 slope, P(ET)CO2, VO2 /Work ratio (ΔVO2/ΔWork). Results: Rehabilitation improved peak VO2, pulse O2, VO2 AT and ΔVO2/ΔWork in all patients by about 13% (p < 0.01). Most patients (126, 62%) showed a reduced left ventricular ejection fraction (HFrEF), but rehabilitation was effective also in patients with mildly reduced (HFmrEF: n = 55, 27%) or preserved ejection fraction (HFpEF: n = 22, 11%). Conclusions: Rehabilitation in patients with heart failure induces a significant recovery of cardiorespiratory performance easily assessed by CPET, that is applicable to the majority of them and should be used routinely in the programming and evaluating of cardiac rehabilitation programs.