La Cardiologia del segle XXI

Les malalties cardiovasculars, juntament amb el càncer, són dos dels àmbits en què s'han concentrat més els recursos sanitaris els darrers anys. Pel que fa a la cardiologia, hi ha hagut grans avenços en àrees com l'intervencionisme, l'electrofisiologia, el diagnòstic i la cirurgia, i això ha creat tot un seguit d'eines terapèutiques que han fet evolucionar molt el tractament de les malalties cardiovasculars. Pel que fa al futur, la cardiologia s'espera que evolucioni envers una medicina més personalitzada, preventiva, predictiva i participativa, en què el pacient serà un actor ple en la diagnosi de la seva malaltia. Tot això ens portarà a l'anomenada medicina de sistemes.Cardiovascular diseases, along with cancer are two of the areas where health resources are more involved in recent years. As for cardiology, there have been major advances in areas such as intervention, electrophysiology, diagnosis and surgery, and this has created a series of therapeutic tools that have make evolve the treatment of cardiovascular diseases. Regarding the future of cardiology, is expected to evolve towards a more personalized, preventive, predictive and participatory medicine, where the patient is a full actor in the diagnosis of the disease. All this leads to the so-called systems medicine

Assessment of electrocardiograms with pretraining and shallow networks

Objective: Clinical Decision Support Systems normally resort to annotated signals for the automatic assessment of ECG signals. In this paper we put forward a new method for the assessment of normal/abnormal heart function from raw ECG signals (i.e. signals without annotation) based on shallow neural networks with pretraining. Methodology: this paper resorts to a prospective clinical study that took place at Hospital Cll´inic in Barcelona, Spain. This study took place in 2010-2012 and recruited 1390 patients. For each patient we recorded a 12-lead ECG and diagnosis was conducted by the Cardiology service at the same hospital. Two datasets were produced, the first contained the automatically annotated version of all input signals and the second contained the raw signals obtained from the ECG. Results: The new method was tested through crossvalidation with a cohort of 200 test patients. Performance was compared for both annotated and raw datasets. For the annotated dataset and a shallow network with pretraining we obtained an accuracy of 0.8639, a sensitivity of 0.9560 and specificity of 0.7143. The raw dataset yielded an accuracy of 0.8426, a sensitivity of 0.8977 and a specificity of 0.7785. Conclusion: Shallow networks with pretraining automatically obtain a representation of the input data without resorting to any annotation and thus simplify the process of assessing normality of ECG signals. Despite the fact that sensitivity has decreased, accuracy is not much lower than that obtained with standard methods. Specificity is improved with the new method. These results open up a promising line of research for the automatic assessment of ECG signals.Peer ReviewedPostprint (published version

Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model

Rationale Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals

Analysis of Three-Dimensional Scar Architecture and Conducting Channels by High-Resolution Contrast-Enhanced Cardiac Magnetic Resonance Imaging in Chagas Heart Disease

We aimed to describe the morphology of the border zone of viable myocardium surrounded by scarring in patients with Chagas heart disease and study their association with clinical events.Adult patients with Chagas heart disease (n=22; 55% females; 65.5 years, SD 10.1) were included. Patients underwent high-resolution contrast-enhanced cardiac magnetic resonance using myocardial delayed enhancement with postprocessing analysis to identify the core scar area and border zone channels number, mass, and length. The association between border zone channel parameters and the combined end-point (cardiovascular mortality or internal cardiac defibrillator implantation) was tested by multivariable Cox proportional hazard regression analyses. The significance level was set at 0.05. Data are presented as the mean (standard deviation [SD]) or median (interquartile range).A total of 44 border zone channels (1[1-3] per patient) were identified. The border zone channel mass per patient was 1.25 (0.48-4.39) g, and the extension in layers of the border zone channels per patient was 2.4 (1.0-4.25). Most border zone channels were identified in the midwall location. Six patients presented the studied end-point during a mean follow-up of 4.9 years (SD 1.6). Border zone channel extension in layers was associated with the studied end-point independent from left ventricular ejection fraction or fibrosis mass (HR=2.03; 95% CI 1.15-3.60).High-resolution contrast-enhanced cardiac magnetic resonance can identify border zone channels in patients with Chagas heart disease. Moreover, border zone channel extension was independently associated with clinical events

Large Genomic Imbalances in Brugada Syndrome

Purpose Brugada syndrome (BrS) is a form of cardiac arrhythmia which may lead to sudden cardiac death. The recommended genetic testing (direct sequencing of SCN5A) uncovers disease-causing SNVs and/or indels in ~20% of cases. Limited information exists about the frequency of copy number variants (CNVs) in SCN5A in BrS patients, and the role of CNVs in BrS-minor genes is a completely unexplored field. Methods 220 BrS patients with negative genetic results were studied to detect CNVs in SCN5A. 63 cases were also screened for CNVs in BrS-minor genes. Studies were performed by Multiplex ligation-dependent probe amplification or Next-Generation Sequencing (NGS). Results The detection rate for CNVs in SCN5A was 0.45% (1/220). The detected imbalance consisted of a duplication from exon 15 to exon 28, and could potentially explain the BrS phenotype. No CNVs were found in BrS-minor genes. Conclusion CNVs in current BrS-related genes are uncommon among BrS patients. However, as these rearrangements may underlie a portion of cases and they undergo unnoticed by traditional sequencing, an appealing alternative to conventional studies in these patients could be targeted NGS, including in a single experiment the study of SNVs, indels and CNVs in all the known BrS-related genes

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Background: Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases. Methods and Findings: Our cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively. Conclusions: Cardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk

Atrial fibrosis in a chronic murine model of obstructive sleep apnea: mechanisms and prevention by mesenchymal stem cells

OSA increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes. However, a causal association is not firmly established and the mechanisms involved are poorly understood. The aims of this work were to determine whether chronic obstructive sleep apnea (OSA) induces an atrial pro-arrhythmogenic substrate and to explore whether mesenchymal stem cells (MSC) are able to prevent it in a rat model of OSA. METHODS: A custom-made setup was used to mimic recurrent OSA-like airway obstructions in rats. OSA-rats (n = 16) were subjected to 15-second obstructions, 60 apneas/hour, 6 hours/day during 21 consecutive days. Sham rats (n = 14) were placed in the setup but no obstructions were applied. In a second series of rats, MSC were administered to OSA-rats and saline to Sham-rats. Myocardial collagen deposit was evaluated in Picrosirius-red stained samples. mRNA expression of genes involved in collagen turnover, inflammation and oxidative stress were quantified by real time PCR. MMP-2 protein levels were quantified by Western Blot. RESULTS: A 43% greater interstitial collagen fraction was observed in the atria, but not in the ventricles, of OSA-rats compared to Sham-rats (Sham 8.32 ± 0.46% vs OSA 11.90 ± 0.59%, P < 0.01). Angiotensin-I Converting Enzyme (ACE) and Interleukin 6 (IL-6) expression were significantly increased in both atria, while Matrix Metalloproteinase-2 (MMP-2) expression was decreased. MSC administration blunted OSA-induced atrial fibrosis (Sham + Saline 8.39 ± 0.56% vs OSA + MSC 9.57 ± 0.31%, P = 0.11), as well as changes in MMP-2 and IL-6 expression. Interleukin 1-β (IL-1β) plasma concentration correlated to atrial but not ventricular fibrosis. Notably, a 2.5-fold increase in IL-1β plasma levels was observed in the OSA group, which was prevented in rats receiving MSC. CONCLUSIONS: OSA induces selective atrial fibrosis in a chronic murine model, which can be mediated in part by the systemic and local inflammation and by decreased collagen-degradation. MSCs transplantation prevents atrial fibrosis, suggesting that these stem cells could counterbalance inflammation in OSA

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine

Accuracy of standard bipolar amplitude voltage thresholds to identify late potential channels in ventricular tachycardia ablation

Background: Ventricular tachycardia (VT) is caused by the presence of a slow conduction channel (CC) of border zone (BZ) tissue inside the scar-core tissue. Electroanatomic mapping can depict this tissue by voltage mapping. Areas of slow conduction can be detected as late potentials (LPs) and their abolition is the most accepted ablation endpoint. In the current guidelines, bipolar voltage thresholds for BZ and core scar are 1.5 and 0.5 mV respectively. The performance of these values is controversial. The aim of the study is to analyze the diagnostic yield of current amplitude thresholds in voltage map to define VT substrate in terms of CCs of LPs. Predictors of usefulness of current thresholds will be analyzed. Methods: All patients with structural heart disease who underwent VT ablation in Hospital Clinic in 2016-2017 were included. Maps with delineation of CCs based on LPs were created with contact force sensor catheter. Thresholds were adjusted for every patient based on CCs. Diagnostic yield and predictors of performance of conventional thresholds were analyzed. Results: During study period, 57 consecutive patients were included (age: 60.4 ± 8.5; 50.2% ischemic cardiomyopathy, LVEF 39.8 ± 13.5%). Cutoff voltages that better identified the scar and BZ according to the LP channels were 0.32 (0.02-2 mV) and 1.84 (0.3-6 mV) respectively. Current voltage thresholds identified correctly core and BZ in 87.7% and 42.1% of the patients respectively. Accuracy was worse in non-ischemic cardiomyopathy (NICM) especially for BZ (28.6% vs 55.2%, p = 0.042). Conclusions: Accuracy of standard voltage thresholds for scar and BZ is poor in terms of LPs detection. Diagnostic yield is worse in NICM patients specially for border zone

Benefit of left atrial roof linear ablation in paroxysmal atrial fibrillation: a prospective, randomized study

Background Isolation of the pulmonary veins (PVs) for the treatment of atrial fibrillation (AF) is often supplemented with linear lesions within the left atrium (LA). However, there are conflicting data on the effects of creating a roof line (RL) joining the superior PVs in paroxysmal atrial fibrillation (PAF). Methods and Results A cohort of 120 patients with drug-refractory PAF referred for ablation were prospectively randomized into 2 strategies: (1) PV isolation in combination with RL ablation (LA roof ablation [LARA]-1: 59 patients) or (2) PV isolation (LARA-2: 61 patients). Follow-up was performed at 1, 3, and 6 months after the procedure and every 6 months thereafter. After a 3-month blanking period, recurrence was defined as the ocurrence of any atrial tachyarrhythmia lasting ≥30 seconds. PV isolation was achieved in 89% and complete RL block in 81%. RF duration, fluoroscopy, and procedural times were slightly, but not significantly, longer in the LARA-1 group. After 15±10 months, there was no difference in the arrhythmia-free survival after a single AF ablation procedure (LARA-1: 59% vs. LARA-2: 56% at 12 months; log rank P=0.77). The achievement of complete RL block did not influence the results. The incidence of LA macroreentrant tachycardias was 5.1% in the LARA-1 group (n=3) versus 8.2% in the LARA-2 (n=5) (P=ns). Univariate analysis only identified AF duration as a covariate associated with arrhythmia recurrence (hazard ratio, 1.01 [95% confidence interval, 1.002 to 1.012]; P<0.01). Conclusion The linear block at the LA roof is not associated with an improved clinical outcome compared with PV isolation alone