Body weights, heart weights and heart weight/body weight ratios at the endpoint.

<p>Groups: Sedentary; Exercise, Sedentary+LOS = sedentary plus losartan; Exercise+LOS = exercise plus losartan. BW = body weight; HW = heart weight; HW/BW = heart weight-to-body weight ratio. Data are mean ± SEM of 6 animals (sedentary and sedentary+LOS) and 6 animals (exercise and exercise+LOS).</p>*<p>p<0.05 exercise group <i>vs</i> sedentary group and</p>†<p>p<0.05 sedentary+LOS <i>vs</i> exercise+LOS.</p

mRNA expression of fibrosis markers in each of the four cardiac chambers.

<p>Results are expressed according to the ΔCt method, with exercise group values in reference to those of the sedentary group (ΔCt ± SEM). Data are means ± SEM of 4 animals (all groups). * p<0.05 sedentary <i>vs</i> exercise; $ p<0.05 sedentary+LOS vs exercise+LOS, and, # p<0.05 exercise <i>vs</i> exercise+LOS.</p

Assessment of right ventricle myocardial fibrosis.

<p>(A) Representative Picrosirius red-stained photomicrographs of the right ventricle, S: sedentary; S+LOS: sedentary plus losartan; E: exercise; E+LOS: exercise+losartan. Magnification ×200. An excess of interstitial collagen deposition (red staining) was observed in the right ventricle of the exercise group. (B) Morphometryc analysis of collagen deposition. Mean ± SEM collagen content in RV. * p<0.05 sedentary <i>vs</i> exercise, # p<0.05 exercise <i>vs</i> exercise+LOS.</p

Protein levels of fibrotic markers in each one of the four cardiac chambers.

<p>Mean ± SEM protein levels of fibrotic markers (A) TGF-β1, (B) Fibronectin-1, (C) MMP-2, (D) TIMP-1, (E) collagen-1, (F) collagen-III analyzed by immunoblot (examples shown above bar graphs) and normalized to β-Actin. (All groups n = 4).</p

Assessment of ventricular hypertrophy.

<p>(A) Representative graph of a tissue slice indicating the three areas of study: right ventricular free wall (RV FW), left ventricular free wall (LV FW) and interventricular septum (IVS). Twelve measures were obtained from each of the areas. (B) Results of ventricular wall thickness indexed for body weight in all the experimental groups. LV FW was significantly higher in all exercise groups compared to sedentary groups. Data are means ± SEM of 6 (sedentary and sedentary+LOS) and 6 (exercise and exercise+LOS). * p<0.05 sedentary <i>vs</i> exercise; $ p<0.05 sedentary+LOS <i>vs</i> exercise+LOS, and, # p<0.05 exercise <i>vs</i> exercise+LOS.</p

Characteristics of the Spanish BrS patients carrying rare genetic variations.

<p>The table shows the clinical characteristics of the probands who carried rare genetic variations in <i>SCN5A</i>, <i>SCN2B</i>, or <i>RANGRF</i>. All of them are potentially pathogenic except that found in <i>RANGRF</i>, which is of unknown significance (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132888#sec014" target="_blank">discussion</a>). All the potentially pathogenic variations (PPVs) that had been previously reported, except p.P1725L and p.R1898C, had been identified in BrS patients. p.P1725L had been associated with Long QT Syndrome and p.R1898C was found in Exome Variant Server with a MAF of 0.0079%. No rare variations were identified in the control population. Patient’s age is expressed in years. Bold identifies the patients carrying variations that had not been described previously. M, male; F, female; S, syncope; ICD, intracardiac cardioverter defibrillator; UK, unknown; EPS, electrophysiological studies (+, positive response;-, negative response; N/P, not performed). The two patients who carried two PPVs each are identified by ^a and ^b, respectively.</p

Influence of the phenotype on PPV discovery yield.

<p>Bar graph comparing the PPV detection yield in 8 different clinical categories (stated below the graph). Each bar shows the total number of patients for each clinical category divided in those with a PPV (black) and those without an identified PPV (white). The number of patients (in brackets) and percentages are given. Pos, positive; Neg, negative; Spont, spontaneous type 1 BrS ECG; Drug, drug-induced type 1 BrS ECG; <i>n</i>, number of patients.</p

Demographics of the 55 Spanish BrS patients included in the study.

<p>The table shows the demographic characteristics of all the patients included in the study. Numbers in parentheses represent the relative percentages for each condition. T1 ECG refers to Type 1 BrS diagnostic electrocardiogram (ECG), obtained either spontaneously, or after drug challenge. The information regarding both the electrophysiological studies (EPS) and the treatment was not available for all the patients. Two of the patients that didn’t receive any treatment died, and were not taken into account for the calculations of percentages (+2 dead). ICD, intracardiac cardioverter defibrillator.</p

Na_v1.5 channel scheme showing the relative position of the <i>SCN5A</i> PPVs identified in our cohort.

<p>Open symbols indicate already described variations and closed symbols locate novel variations reported in this study. DI to DIV designate the 4 domains of the protein, and numbers 1–6 identify the different segments within each domain. Crosses mark the voltage sensor.</p

Influence of the age on PPVs discovery yield.

<p><b>(A)</b> Pie charts showing the distribution of patients in the overall population as well as in the categories of symptomatic and asymptomatic patients regarding PPV discovery. The percentage and the number of patients (in brackets) are given for each group. The small pie charts correspond to the age distribution of patients with an identified PPV. <b>(B)</b> Bar graphs of the PPV detection yields obtained for each of the age groups (< 30 years, 30–50 years and > 50 years). Numbers inside each bar correspond to the number of patients carrying a PPV for each category and the percentages represent the variation detection yield.</p