Background and objectives: Long standing hypothyroidism may impair myocardial relaxation, but its effect on systolic myocardial function is still controversial. The aim of this study was to investigate left ventricular (LV) systolic and diastolic function in patients with hypothyroidism. Materials and Methods: This study included 81  patients with hypothyroidism, and 22 age and gender matched controls. All subjects underwent a detailed clinical examination followed by a complete biochemical blood analysis including thyroid function assessment and anthropometric parameters measurements. LV function was assessed by 2-dimensional, M-mode and Tissue-Doppler Doppler echocardiographic examination performed in the same day. Results: Patients had lower waist/hip ratio (p< 0.001), higher urea level (p = 0.002), and lower white blood cells (p = 0.011), compared with controls. All other clinical, biochemical, and anthropometric data did not differ between the two groups. Patients had impaired LV diastolic function , compared with controls. Although LV global systolic function did not differ between groups, LV longitudinal systolic function was compromised in patients . Conclusions: In patients with hypothyroidism, in addition to compromised LV diastolic function, LV longitudinal systolic function is also impaired compared to healthy subjects of the same age and gender. These findings suggest significant subendocardial function impairment, reflecting potentially micro-circulation disease that requires optimum management. Hypothyroidism is an endocrine disorder, caused by thyroid hormone deficiency, which may affect the heart and the cardiovascular system. Thyroid hormones assist in maintaining low peripheral resistance in peripheral arterioles through a direct effect on vascular smooth muscles, thus increasing blood volume, systemic vascular resistance, preload, and cardiac output in patients with hyperthyroidism .In contrast, hypothyroidism have an opposite effect on the cardiovascular system and may reduce cardiac output by 30–50% . It has The aim of this study was to investigate the effect of hypothyroidism on left ventricular (LV) systolic and diastolic function components using conventional Doppler echocardiography.This study included 81 consecutive patients  diagnosed with clinical hypothyroidism at the Outpatient Endocrinology Clinic of the University Clinical Centre of Kosovo, and 22 subjects, with normal thyroid and renal function who served as a control group, recruited between May 2017 and March 2018. All subjects gave informed consent to participate in the study, which was approved by the Ethics Committee of Medical Faculty, University of Prishtina, with reference number 4056, date 20 June 2014. All included patients had been diagnosed with hypothyroidism depending on thyroid hormone levels and clinical examination by an experienced endocrinologist. Patients with decompensated heart failure, active malignancy, hepatic or pulmonary disease, pregnant women, and those with arterial hypertension were excluded.2). Blood pressure was recorded with a brachial sphygmomanometer, after the subject had rested in the supine position for at least 10 min.In all participants, demographic details, physical examination and anthropometric measurements were taken. Hypothyroidism was defined by low serum T3, T4 levels, high serum thyroid-stimulating hormone (TSH) level, and elevated circulating anti-peroxidase level. Body mass index (BMI) was measured and was calculated by dividing dry weight by body height (kg/m® E 411 Roche). All samples for a given assay were tested simultaneously, in duplicate and in appropriate dilutions, according to conventional protocols.Erythrocyte sedimentation rate, hematological investigations, fasting plasma glucose, blood urea nitrogen (BUN), creatinine, total cholesterol, and triglyceride were measured using standard methods. Thyroid hormones and anti-peroxidase were measured by Electrochemiluminescence (COBAS INTEGRA2.7 (LVMI) [LV structure measurements: Echocardiographic examinations were performed in all patients and controls at the same day of blood tests. LV volumes and ejection fraction (EF) were calculated from the apical 2- and 4-chamber views using the modified Simpson’s method. Left ventricular mass (LVM) was estimated using the anatomically validated formula of Devereux et al. ,13 and w7 (LVMI) :LVM(g) =2.7 for women and 53 g/m2.7 for men [2.Left ventricular hypertrophy (LVH) was defined as a LVMI of 47 g/m for men . LVM norLV function measurements: From the spectral wave Doppler LV filling, peak E wave velocity, peak A wave velocity, the ratio between peak E and A velocities (E/A ratio), and E wave deceleration time were all measured. From tissue-Doppler imaging recordings, peak systolic (s’), early diastolic (e’), and late diastolic (a’) mitral annular velocities were also measured. The ratio of trans-mitral to myocardial early diastolic peak velocity (E/e’) was calculated, having averaged septal and lateral e’ velocities ,17, to rTotal LV filling time (FT) was measured from the onset of the E wave to the end of the A wave and ejection time (ET) from the onset to the end of the aortic Doppler flow velocity. Total isovolumic time (t-IVT) was calculated as 60— and was expressed in s/min . Tei indLeft atrial (LA) measurements: LA diameter was measured from aortic root recordings with the M-mode cursor positioned at the level of the aortic valve leaflets.We followed the methods of our previous study, Poniku A et al. 2018 , which dt test following the analysis of variance. The Chi-square test was used to compare the categorical variables. p values <0.05 were considered statistically significant. All analyses were performed using SPSS 22 for Windows.Values are expressed as means ± standard deviation (SD). Differences between the two groups were analyzed using the unpaired Student p < 0.001), lower RBC (p = 0.019), and lower WBC (p = 0.011) compared to controls.p < 0.001, for both), and lower lateral MAPSE (p = 0.002), compared to controls , lower E wave velocity, lower E/A ratio , lower E/e’ ratio, and longer E wave DT (p = 0.01), compared to controls  and its systolic velocity. In addition, markers of LV diastolic function assessed by spectral Doppler were also quite abnormal with reduced E wave velocity, raised A wave velocity, and reduced E/A ratio, compared to controls. Other conventional measurements of LV structure and function including ejection fraction, stroke volume, LV mass, and synchronous function were not different when compared with controls.Despite rather similar atherosclerosis risk factors, hypertension, diabetes, dyslipidemia and smoking, between groups, patients had significant evidence for impaired LV long axis systolic function which is known to determine, to a large extent, the overall cavity diastolic performance as shown by spectral Doppler in our patients. LV long axis function is subtended by the longitudinal myocardial fibers that constitute the subendocardial layer of the myocardium. This layer is known to be the most sensitive to ischemia, being vascularized by the distal coronary arterioles and capillaries . Having Although having small clinical implication, hypothyroidism is associated with significant cardiac function impairment particularly at the subendocardial level, both in systole and diastole. As long as the endocrine pathology is active, the cardiac disturbances are likely to be perpetual, even irreversible. Identifying such patients with impaired cardiac function early on, should guide towards optimum correction of thyroid function and hence saving future irreversible cardiac dysfunction.The small number of studied patients and controls reduces the strength of the findings and their clinical application. These remain to be reconfirmed in a larger cohort of patients. A larger group of patients with different hypothyroid severities should assist in identifying clearer relationship with different degrees of LV dysfunction as well as cut-off values that require aggressive treatment. We did not have the possibility of using more advanced techniques for assessing cardiac function, e.g., speckle tracking echocardiography, which might have shed more light on other disturbances.In a modest sample of patients with hypothyroidism, in addition to compromised LV diastolic function, LV longitudinal systolic function is also impaired compared to healthy age and gender matched controls. These findings suggest significant subendocardial function impairment, potentially reflecting micro-circulation disease that requires optimum management.


Ivabradine is a pharmacological agent used in patients with heart failure and sinus rhythm. Its only known pharmacological effect is to slow the heart rate. In this study, we investigated the impact of ivabradine on dyssynchrony parameters in heart failure patients.In this study, we assigned 55 patients taking medication for heart failure to receive ivabradine in addition (Group I). Twenty healthy volunteers comprised Group II. Echocardiographic measurements  were taken at baseline, 1 month, and 3 months.P = .001) and to 30.7 ± 19.4 milliseconds at 3 months (P < .001). Septal to posterior wall motion delay decreased from 90.3 ± 21.4 milliseconds to 83.9 ± 26.9 milliseconds (P = .011) at 1 month and to 81.5 ± 27.3 milliseconds at 3 months (P = .001). Septal to lateral Ts delay (Ts‐SL) decreased from 42.7 ± 24.5 milliseconds to 35.8 ± 22.6 milliseconds at 1 month (P < .001) and to 34.8 ± 22.4 milliseconds at 3 months (P = .002). Left ventricular end‐systolic volume (LVESV) decreased from 139.4 ± 42.2 mL to 135.3 ± 39.6 mL at 1 month (P = .006) and to 123.3 ± 39.5 mL at 3 months (P < .001).A total of 32 heart failure patients in Group I completed the study. There was significant improvement in dyssynchrony parameters after ivabradine treatment in Group I. Interventricular dyssynchrony (IVD) decreased from 42.0 ± 24.4 milliseconds at baseline to 33.6 ± 20.7 milliseconds at 1 month (The addition of ivabradine to heart failure treatment improves cardiac dyssynchrony parameters in chronic systolic heart failure patients with sinus rhythm. Ivabradine is only known pharmacological effect is to slow the heart rate. We investigated the impact of ivabradine on dyssynchrony parameters in heart failure patients. The addition of ivabradine to heart failure treatment improves cardiac dyssynchrony parameters in chronic systolic heart failure patients with sinus rhythm. Healthy age‐matched volunteers without heart failure were included in the control group. The criteria for inclusion were: (a) sinus rhythm, (b) LV ejection fraction ≤35%, (c) New York Heart Association (NYHA) functional class II‐IV, (d) resting heart rate ≥70 beats/min. We excluded patients with severe bradycardia due to ivabradine treatment during the study, history of cardiac resynchronization therapy (CRT) or convenient to CRT, pacemaker implantation, congenital heart disease, primary severe valve pathology, recent myocardial infarction (<2 months), and atrial fibrillation or flutter. All patients signed an informed consent form approved by our institutional review board and ethics committee. The study population was divided two groups, Group I consist of 32 reduced EF heart failure patients and Group II consist of 20 healty volunteers.2.2Group I patients continued the classic heart failure treatment suggested by their doctors, including beta‐blockers, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), diuretics, and digoxin. Group II patients received no medication. Ivabradine was initiated after baseline echocardiography. The starting dose was 10 mg/d (5 mg twice daily), which was uptitrated to a target dose of 15 mg/d. The use of medication was checked at 1 month and 3 months.2.3All enrolled patients underwent echocardiography before and 1 month and 3 months after randomization. All imaging was performed using Vivid‐3 Pro, GE Vingmed Ultrasound in two centers and Vivid‐7, GE Vingmed Ultrasound with a 2.5 MHz probe in one center. Transthoracic echocardiography was performed by experienced echocardiography specialists who were blinded to heart failure status. An intraobserver variability study on SPWMD and Ts‐SL time among 10 volunteers showed coefficients of variation in 3.9% and 4,2%, respectively. Between observers, this coefficient was 5.6% and 6.9%. Two‐dimensional and M‐mode echocardiograms were recorded as recommended by the American Society of Echocardiography. Left ventricular end‐systolic and end‐diastolic volumes (LVESV and LVEDV) and left ventricular ejection fraction (LVEF) were calculated from apical two‐ and four‐chamber images using Simpson's biplane technique.2.3.1Pulsed wave Doppler was used for the measurement of interventricular dyssynchrony (IVD). The difference between preejection intervals of the left ventricular and right ventricular outflow tracts was calculated with the initiation of electrocardiographic QRS.2.3.2Septal to posterior wall motion delay (SPWMD) was calculated from the parasternal long‐axis view using M‐mode echocardiography.Basal septal and basal lateral myocardial velocities were measured from the apical four‐chamber view. Segment time (Ts) was measured as the duration from the initiation of QRS to peak systolic myocardial velocity, and septal to lateral Ts delay (Ts‐SL) was calculated.All measurements were corrected for heart rate using Bazett's formula to avoid the confounding effect of heart rate changes. Differences between the parameters at baseline and at 3 months were calculated and recorded as “delta” .2.4t test for continuous variables and the chi‐square test for categorical variables. Changes in echocardiographic parameters between baseline, at 1 month and 3 months in Group I were compared with repeated measurement analysis of variance. Pearson's or Spearman's correlation analysis was used to test associations between the changes in echocardiographic parameters between baseline and 3 months and the other parameters. A P value < .05 was considered statistically significant.The Statistical Package for Social Sciences, version 15.0 was used for statistical analysis. Data were expressed as mean ± standard deviation for continuous variables, and as numbers (percentages) for categorical variables. Kolmogorov‐Smirnov test was used to evaluate whether continuous variables were normally distributed. Group I and Group II variables were compared using Student's 3Fifty‐five heart failure patients were enrolled in the study, 23 of whom did not complete the study: Six were unable to come to appointments, five developed atrial fibrillation, three were unable to continue ivabradine treatment because of bradycardia (<50 beats/min), five patients died and four patients had CRT. As a result, the study included a total of 32 heart failure patients and 20 healthy volunteers. Seven patients had symptomatic bradycardia during the study and ivabradine was stopped in three patients (5.4%) due to persistent bradycardia (<50 beats/min) despite dose titration. None of the patients had a transient or permanent pacemaker.Baseline characteristics of the patients are given in Table 3.1P < .001) at 1 month, and 63.5 ± 11.2 beats/min at 3 months (P < .001). In Group I, LV ejection fraction was 31.3 ± 5.6% at baseline, 32.4 ± 5.8% (P < .05) at 1 month, and 34.9 ± 7.5% at 3 months (P < .001).In Group I, LV end‐diastolic volume was 201 ± 54mL at baseline, 193.7 ± 48.9 mL (P < .05) at 1 month, and 187.5 ± 48.3 mL at 3 months (P < .001). In Group, I LV end‐systolic volume was 139.4 ± 42.2 mL at baseline, 132.1 ± 39.2 mL (P < .05) at 1 month, and 123.3 ± 39.5 mL at 3 months (P < .001). In Group I, interventricular dyssynchrony was 42.0 ± 24.4 milliseconds at baseline, 33.6 ± 20.7 milliseconds (P < .05) at 1 month, and 30.7 ± 19.4 milliseconds at 3 months (P = .002). In Group I, septal to posterior wall motion delay was 90.3 ± 21.4 milliseconds at baseline, 83.9 ± 26.9 milliseconds (P < .05) at 1 month, and 81.5 ± 27.3 milliseconds at 3 months (P = .001). In Group I, septal to lateral Ts delay was 42.7 ± 24.5 milliseconds at baseline, 35.8 ± 22.6 milliseconds (P < .05) at 1 month, and 34.8 ± 22.4 milliseconds at 3 months (P = .002). In Group I, there were 19 NYHA III–IV class patients at baseline, 8 at 1 month (P = .011), and 3 at 3 months (P = .002)  (Table P = .011), and 81.5 ± 27.3 milliseconds (P = .001) at 3 months. Ts‐SL was 42.7 ± 24.5 milliseconds at baseline, 35.8 ± 22.6 milliseconds at 1 month (P < .001), and 34.8 ± 22.4 milliseconds at 3 months (P = .002)  at baseline, and had decreased to 33.6 ± 20.7 milliseconds (P = .001) at 1 month and 30.7 ± 19.4 milliseconds (P < .001) at 3 months . LVEF increased from 31.3 ± 5.6% at baseline to 32.0 ± 5.6% at 1 month (P = .061) and 34.9 ± 7.5% (P < .001) at 3 months. LVEDV decreased from 201.4 ± 52.4 mL to 195.9 ± 50.7 mL at 1 month (P = .103) and 187.5 ± 48.3 mL (P < .001) at 3 months. LVESV decreased from 139.4 ± 42.2 mL to 135.3 ± 39.6 mL (P = .006) at 1 month and 123.3 ± 39.5 mL (P < .001) at 3 months (Table P = .001), delta SPWMD , delta Ts‐SL , and delta HR  were significant .Ivabradine is a pharmacological agent which inhibits the Cardiac remodeling is a central feature of the progression of heart failure. In our study, the addition of ivabradine to heart failure treatment led to improvement in cardiac remodeling. Our results are evidence of the relationship between heart rate and cardiac remodeling. Also in a subgroup analysis of the SHIFT study, ivabradine treatment improved cardiac remodeling.In our study, the reduction in heart rate was related to improvement in cardiac dyssynchrony parameters in chronic heart failure patients with sinus rhythm. Beta‐blockers have been shown to improve cardiac dyssynchrony in a limited number of studies4.1Ours was an observational study in a limited number of heart failure patients. Also the etiologies of heart failure and QRS duration were not homogeneous in the patients. Moreover, the lack of a heart failure group which was not treated with ivabradine renders the attribution of improvement in dyssynchrony to ivabradine more difficult.5This study shows that effective heart rate reduction with ivabradine treatment improves cardiac dyssynchrony and cardiac remodeling. Cardiac electrical remodeling accompanied by heart rate reduction could explain the effect of ivabradine in the treatment of heart failure. However, these findings need to be validated in larger and more homogeneous patient groups.None declared.


Multiple circulatory factors are increased in heart failure (HF). Many have been linked to cardiac and/or skeletal muscle tissue processes, which in turn might influence physical activity and/or capacity during HF. This study aimed to provide a better understanding of the mechanisms linking HF with the loss of peripheral function.n = 66) and controls (n = 28). Plasma circulatory factors were quantified using a multiplex immunoassay. Multivariate  and univariate analyses identified many factors that differed significantly between HF and control subjects, mainly involving biological functions related to cell growth and cell adhesion, extracellular matrix organization, angiogenesis, and inflammation. Then, using principal component analysis, links between circulatory factors and physical capacity, daily physical activity, and myocardial function were identified. A subset of ten biomarkers differentially expressed in patients with HF vs controls covaried with physical capacity, daily physical activity, and myocardial function; eight of these also carried prognostic value. These included established plasma biomarkers of HF, such as NT-proBNP and ST2 along with recently identified factors such as GDF15, IGFBP7, and TfR, as well as a new factor, galectin-4.Physical capacity measured by maximum oxygen uptake, myocardial function (measured by echocardiography), physical activity (measured by accelerometry), and mortality data was collected for patients with severe symptomatic heart failure an ejection fraction < 35%  contains supplementary material, which is available to authorized users. VO2peak) , clinical examination and exercise test , and daily physical activity  were analyzed. All variables were scaled to unit variance and mean-centered. The concentrations of the Proseek biomarkers are expressed as arbitrary units and were mean-centered prior to analysis because of the lack of specific calibrators for the assays. Principal components were calculated using the ‘prcomp’ function in the R statistics package , and biplots were generated using the ‘factominer’ and ‘ggplot2’ libraries. Ontological enrichment analysis was performed using the web-based Database for Annotation, Visualization, and Integrated Discovery (DAVID).Given the large set of variables, the reduction of the dimension of our covariate list was performed through variable clustering and dimensionality reduction through PCA Bi plots was used to characterize the variance of the individual variables and to identify collinearities. Variables derived from echocardiographic assessment . In addition to this multivariate approach, the TEN network factors were also tested for prognostic value one-by-one in a Cox regression analysis, both as single independent variables and controlling for important confounders  in the patients with HF were validated with respect to their prognostic capacity in the current cohort. Of the 39 differently expressed circulating factors in the patients with HF, 34 were associated with at least one of the physiological variables measured also when analyzed in the patient group only. A subset of 17 factors covaried with myocardial function, physical capacity, and daily physical activity, of which 10 differed between patients with HF and controls. Eight of these factors ultimately contained prognostic information. This group included well-established  and more recently recognized  plasma biomarkers of HF, together with factors recently associated with this disease  and one factor that was only just now linked to HF  [Using a systems biology approach, we examined potential links between circulatory factors, physical capacity, physical activity, myocardial function, and mortality in patients with HF. Thirty-nine circulatory factors differed significantly between patients with HF and controls. Established prognostic markers (ectin-4) .VO2peak, heart rate, MAP, and daily physical activity confirmed their correlations with prognosis, supporting the clinical measurements as valid, as well as this HF cohort as a valid representation of the general HF with reduced ejection fraction population. The multi- (OPLS-DA) and univariate analyses identified a substantial number of factors that differed significantly between the two groups. This finding confirmed earlier hypothesis-driven ‘single-factor’ studies reporting increased circulatory levels of NT-proBNP [The overall aim of this study was to identify plausible circulatory factors linking reduced myocardial function to changes in peripheral tissue functions. The mutual relationships between echocardiographic measurements of myocardial function, T-proBNP , 76, ST2T-proBNP , 55, GDFT-proBNP , 69, 80,T-proBNP , 31, 58 T-proBNP . After dT-proBNP . InteresOf the 17 factors connected to all three physiological categories, 10 were distinctly higher in patients with HF than controls, and of these, eight carried prognostic information. NT-proBNP was among these. NT-proBNP has a well-documented, strong prognostic value , and a cGDF15, IGFBP7, and TfR1 are three more recently identified factors showing covariance with all three components of analysis that carry prognostic information, and were distinctly elevated in patients with HF vs controls. GDF15 appears to increase with the severity of HF disease , and hasGalectin-4  levels were higher in patients with HF vs controls, they covaried with the three components of analysis employed, and carried prognostic value. To our knowledge, only one previous study has put forward a potential link between circulating Gal-4 and HF  and the Despite the effort made to design and conduct an integrative investigation analyzing factors related to function and prognosis of HF, this study had some limitations that need to be acknowledged. In contrast to other studies with nontargeted approaches, the analytical strategy used here did not identify possible pathophysiological and prognostic markers that are unrelated to physical capacity, physical activity, and echocardiographic estimates of disease severity. Moreover, the samples analyzed in this study originated from a homogeneous cohort of elderly patients of European origin with severe HF from a single center, which might limit the external validity of the results. In addition, several potentially confounding features differed between the patient and the control group. Because the proximity extension assay used here to quantify the biomarkers does not allow an absolute quantification of the target proteins, translation into clinically relevant cutoff values is not possible. In addition, mainly because of the availability and quality of antibodies, there are several biomarkers associated with cardiovascular disease or inflammation that are not incorporated in the current multiplex PEA chip. Because the PEA is a form of widespan-targeted analysis, consisting of a curated panel of factors selected for potential relevance in the context of cardiovascular disease, bias is introduced into the analysis, in which inflammatory factors and markers known to be sensitive to cardiac stretch are highly enriched. Therefore, the networks generated could be biased toward these biological functions. Notwithstanding these limitations, we believe that our investigation contributes new understanding of the molecular networks linking the failing heart and the loss of peripheral function in patients with HF.This study adds novel and important information about circulatory factors that might link the failing myocardium to the loss of peripheral function. We were able to identify several factors that likely participate in the central–peripheral pathogenesis of HF disease, using a systems biology approach relating echocardiographic assessment of myocardial function, physical capacity, and daily physical activity with the concentrations of circulatory factors that differed in patients with HF vs controls, and Cox regression analysis of mortality. Some of these factors are well-known, validated biomarkers for HF , while others are either relatively or completely new in this field . Overall, these findings support the importance of systemic circulatory factors linked to hemodynamic systemic stress and inflammatory responses in the pathogenesis and progress of HF disease.Supplementary file1 (DOCX 14 kb)Below is the link to the electronic supplementary material.


A considerable number of non-ischemic dilated cardiomyopathy (NDCM) patients had been found to have normalized left ventricular (LV) size and systolic function with tailored medical treatments. Accordingly, we aimed to evaluate if strain parameters assessed by cardiovascular magnetic resonance (CMR) feature tracking (FT) analysis could predict the NDCM recovery.79 newly diagnosed NDCM patients who underwent baseline and follow-up CMR scans were enrolled. Recovery was defined as a current normalized LV size and systolic function evaluated by CMR.api/bas) and a lower standard deviation of time to peak radial strain in 16 segments of the LV (SD16-TTPRS). According to a multivariate logistic regression model, RSapi/bas (P = 0.035) and SD16-TTPRS (P = 0.012) resulted as significant predictors for differentiation of recovered from unrecovered patients. The sensitivity and specificity of RSapi/bas and SD16-TTPRS for predicting recovered conditions were 76%, 67%, and 91%, 59%, with the area under the curve of 0.75 and 0.76, respectively. Further, Kaplan Meier survival analysis showed that patients with RSapi/bas ≥ 0.95% and SD16-FTPRS ≤ 111 ms had the highest recovery rate .Among 79 patients, 21 (27%) were confirmed recovered at a median follow-up of 36 months. Recovered patients presented with faster heart rates (HR) and larger body surface area (BSA) at baseline (P < 0.05). Compared to unrecovered patients, recovered pateints had a higher LV apical radial strain divided by basal radial strain (RSapi/bas and CMR SD16-TTPRS may be used as non-invasive parameters for predicting LV recovery in NDCM. This finding may be beneficial for subsequent treatments and prognosis of NDCM patients. Registration number: ChiCTR-POC-17012586.RS Non-ischemic dilated cardiomyopathy (NDCM) is a condition that manifests as the enlargement of the left ventricle (LV) or both ventricles with systolic dysfunction or abnormal loading conditions . As one With excellent spatial resolution and high reproducibility, cardiovascular magnetic resonance (CMR) is considered the non-invasive gold standard for evaluating cardiac function and myocardial contraction . Nowaday2; (3) HF secondary to chronic lung disease; (4) valvular disease of moderate or greater severity; (5) active myocarditis; (6) other cardiomyopathies  [A total of 120 newly diagnosed (symptoms occurred within 2 months) NDCM patients based on the 1995 World Health Organization/International Society and Federation of Cardiology criteria [iseases) . In addiA median interval of 36 months  between the enrollment and follow-up CMR(n = 79) were used to classify patients into two groups. Recovery was defined as a current LVEF of ≥ 50% and a CMR LV end-diastolic volume indexed to body surface area (LVEDVI) within the normal range; and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration less than 250 ng/L , 14. TheThe study was approved by the Ethics Committee of Shanghai Jiaotong University Affiliated No.6 Hospital. Written informed consent was obtained from all participants.2, acquisition matrix 232 × 219; 30 phases per cardiac cycle). Late gadolinium enhancement (LGE) imaging was performed 10 min after injection of 0.2 mmol/kg of contrast .ECG-gated CMR studies were performed on a 3T CMR system . Balanced steady-state free precision (bSSFP) cines were acquired in three long-axis slices . Subsequent short-axis cines extending from the mitral valve ring to the apex were obtained to cover the entire LV ; end-systolic volume (LVESV)), LVEF, right ventricular (RV) ejection fraction (RVEF), and LV mass (LVM) were performed using standardized protocols and dedicated software . LVM was estimated at end-diastole and corroborated at end-systole, which excluded the papillary muscles. LV cardiac index (CI) was calculated according to the formula below: CI =  formula .api/bas, RSapi/bas) were calculated as apical strain divided by basal strain, respectively. Instantaneous LV peak torsion was defined as the maximum difference in rotation angle between the base and apex divided by the distance between apical and basal slices automatically  analysis was performed on the standard acquired bSSFP cine images using cvi42 (Circle Cardiovascular Imaging). LV endocardial and epicardial borders were automatically tracked and manually corrected in three long-axis slices and in short-axis slices in the end-diastolic phase. RV endocardial and epicardial borders were manually traced in the end-diastolic phase in long-axis slices and in short-axis slices. Left atrial (LA) endocardial and epicardial borders were manually traced in the apical four-chamber and apical two-chamber views at end-systole . Global Quantitative assessment of myocardial fibrosis was performed on LGE imaging data on short-axis images using cvi42 (Circle Cardiovascular Imaging). Normal myocardium was visually defined as a region of myocardium without any apparent LGE on visual inspection. The mean signal intensity and standard deviation (SD) were determined by drawing a region of interest (ROI) in a portion of the normal myocardium on each slice. The semi-automated greyscale threshold technique was performed by using 2, 4, 6 SD above the mean signal intensity for the normal nulled myocardium. Results were reported as the percentage of LGE mass to the total LVM .Data from 10 healthy subjects and 10 NDCM patients were applied to test inter- and intraobserver variability. 2 independent cardiologists (***1 and ***2) specialized in CMR were blinded to each other’s recordings and conducted separate CMR analyses. All CMR measurements were analyzed by both observers. Data from the separate acquisitions were used to test interobserver variability. In order to test intraobserver variability, the observers re-analyzed their own recordings (3 weeks apart).api/bas, SD16-FTPRS) were included in the model with the predictive accuracy of 81%. Receiver-operating characteristic curve analysis was used to identify parameters that were best fit in diagnosing the recovered model of NDCM. The best cutoff value was based on the maximum Youden index. The Kaplan Meier survival analysis was applied to calculate the recovery rate. The intraclass correlation coefficient (ICC) was used to determine inter- and intraobserver reproducibility. All calculations were performed using SPSS .Summary statistics of clinical and image data were expressed as mean ± SD, median (quartile25–quartile75) or percentage, as appropriate. Comparisons between groups were made using one-way ANOVA analysis for continuous, normally distributed data and Wilcoxon rank-sum test for continuous, non-normally distributed data. The bonferroni correction was made for multiple comparisons. The chi-square test or Fisher’s exact test was calculated for categorical variables. Univariate and multivariate logistic regression analyses were performed to identify prognostic predictors for the recovered condition. Considering the collinearity and clinical significance, 4 variables (heart rate (HR), BSA, RSBaseline CMR test, available baseline, and follow-up data from 79 NDCM patients were analyzed . Recovery in both LV size and LVEF was observed in 21 out of 79 patients  compared with the other 58 patients . No differences in medications were observed between the recovered and unrecovered group. The recovered group patients showed faster baseline HR , larger BSA , and higher hemoglobin (Hb) . The baseline clinical variables of the study groups are presented in Table Baseline CMR parameters including LVEDVI, LVESV indexed to BSA (LVESVI), LVEF, LV stroke volume indexed to BSA (SVI), CI, LVM indexed to BSA (LVMI), and RVEF were similar between two NDCM groups. The qualitative LGE analysis was also similar. While follow-up CMR parameters of the recovered patients, including LVMI, LVEDVI, LVESVI, LVEF, and CI, were closer to those observed in healthy control subjects and were different when compared with unrecovered NDCM patients. CMR parameters are listed in Table bas, CSmid, and RSbas, RSmid) were similar between two NDCM groups, but the apical strains were significantly lower in the unrecovered group  were substituted into the multivariate logistic regression model, which revealed that the recovered group was correlated with RSapi/bas  and SD16-TTPRS    27% NDCM patients had normalized LV size and systolic function after a median 36 months; (2) conventional LV systolic function parameters were similar between the recovered and unrecovered NDCM groups at baseline; (3) myocardial contractility at apical and intraventricular mechanical coordination were much better in recovered patients at baseline using CMR FT analysis, of which RSSeveral studies have shown that the recovered condition incidence ranges from 14 to 41% in NDCM patients –5. In ouLVEF, reflecting global LV systolic function, is a universal marker for routine risk stratification and therapeutic strategy decision in patients with NDCM. In this study, the CMR examination revealed no difference in LVEF at baseline in the two NDCM groups. LVEF only revealed the variation of global and accumulative LV volume and function, which later changes in the pathological process and lacks sensitivity and specificity to predict the disease’s subsequent prognosis. More delicate and accurate parameters are required to further discriminate NDCM patients.api/bas and RSapi/bas compared to unrecovered. In other words, the heterogeneity of contractile injury exists in patients with NDCM. Similar to our results, Bach et al. [LV deformation is expressed as strain, which represents the fractional or percentage change of a region of interest from its original dimension . In thish et al.  found thh et al. , 22. ThiMoreover, the decreased contractility of the localized part and the loss of consistency of regional myocardium could also affect systolic function, which may directly weaken the cardiac pump. Therefore, more research is focusing on mechanical synchronism. Our study demonstrated that significant intraventricular mechanical dyssynchrony in regional longitudinal, circumferential, and radial dimensions were detected in unrecovered patients, and the difference was more obvious in the radial dimension. On the contrary, better mechanical synchronization was found in recovered patients; however, it was not as homogeneous as in control subjects, whose septum contracts slightly earlier than the lateral and inferolateral walls . Intraveapi/bas and SD16-TTPRS assessed by CMR at presentation may prove to be non-invasive parameters for prediction of recovery in patients with NDCM. Global and segmental strains of the recovered NDCM patients will be analyzed and reported in our post-study, which may offer greater insight into the disease.To the best of our knowledge, this is the first study that reported on the use of CMR FT strain analysis for prediction of functional recovery in NDCM patients. We found 27 % of NDCM patients had recovered LV size and systolic function in this cohort. RSapi/bas and SD16-FTPRS predict recovery, the area under the curve for each variable was below 0.80. More markers such as native T1 or extracellular volume fraction could not be performed, as both were not available in the majority of the patients. It remains unknown how much longer the recovered NDCM patients could maintain their morphologic and functional recovery. Long-term follow-up and molecular studies are needed to make a preliminary stratification of those patients at presentation.The present study has several limitations. As this was a single-center study, the sample size was modest. Though RSThis study highlights the prevalence of the recovered condition in NDCM patients. Strain analysis using CMR FT imaging is considered a useful method to evaluate NDCM patients’ prognosis. Further prospective multicenter studies are needed to certify whether CMR strain assessed can be used to predict long-term prognosis in NDCM patients .Additional file 1. Calculation of torsional shear angle from basal and apical slices.


This study examined the impact of septal flattening on left ventricular (LV) torsion in patients with precapillary pulmonary hypertension (PH). Fifty-two patients with proven precapillary PH and 13 healthy controls were included. Ventricular function was assessed including 4D-measurements, tissue velocity imaging, and speckle tracking analysis. Increased eccentricity index , systolic pulmonary artery pressure  and right ventricular Tei index , and reduced tricuspid annular plane systolic excursion  were detected in PH patients as compared to controls. With increasing eccentricity of left ventricle, LV torsion was both decreased and delayed. Torsion rate paralleled this pattern of change during systole, but not during diastole. In conclusion, right ventricular pressure overload directly affects LV torsion mechanics. The echocardiographic methodology applied provides novel insights in the interrelation of right- and left ventricular function. Left and right ventricle reside in the confined space of the pericardium. In response to right ventricle enlargement, the interventricular septum (IVS) will shift leftwards . This phPrevious echocardiographic studies in pulmonary hypertension mainly focused on right ventricular mechanics changes, relatively little is known regarding the interventricular interaction and the mechanical effects of the D-sign on the function of left ventricle. The D-sign not only reflects shear mechanical impact of the pressure overloaded right ventricle, but might also impair interventricular interaction. It might be speculated that compression of the left ventricle due to enlarged right ventricle might also diminish left ventricular function, the findings of preliminary earlier studies hinted this speculation . HoweverEarlier studies focusing on the interrelation of left and right ventricular function revealed that about 20% to 40% of the right ventricular systolic pressure and volume outflow result from left ventricular contraction [To overcome this limitation, planimetric methods such as the Simpson formula have been developed, taking into account the radial function as well as the longitudinal shortening of the left ventricle for better evaluation of left ventricular function. Newer techniques have been developed to recognize and better differentiate the individual disturbed components contributing to diminished ventricular function. Nowadays, the field of vectorized deformation techniques came into the focus of echocardiographic research. Spatial deformation of the myocardium can be divided into longitudinal, radial and circumferential components, and these components could be evaluated by novel techniques such as tissue velocity imaging (TVI) or speckle tracking echocardiography (STE). In short axis views of the left ventricle, STE can be used to quantify the rotation of the basal, middle and apical segments around the longitudinal axis through evaluating the contraction mode of the inner and outer myocardial layers. These layers contain diagonal fibers, and contraction of diagonal fibers could lead to both longitudinal shortening and twisting motion of the left ventricle. By measuring the apical and basal rotation in relation to the mid segments, torsion can be quantified as the difference of both movements in degrees. This motion contributes up to 20% of left ventricular systolic function and might be essential for evaluation of diastolic function. From this raw measurement, torsion is derived by normalization of ventricular length. The temporal derivations of these parameters are known as torsion rate and twist rate, respectively. Association of systolic torsion rate with left ventricular inotropy and maximal untwisting rate with left ventricular diastolic function have been described before , 4.In the current study we hypothesized that the shift of the interventricular septum (flatten) not only alters morphology but also disturbs the functional integrity of the left ventricle. First, the natural moving mode of the diagonal fibers might be altered by local impression of the wall, resulting in passive muscular insufficiency of the fibers. Second, the rotational movement of each cross-section might be compromised due to aberration from the usually round geometry. Therefore, we examined the impact of septal flattening on alterations in left ventricular torsion in patients with precapillary PH. In clinical practice, assessment of left ventricular torsion might add to the outcome evaluation of precapillary PH patients.In this retrospective cohort study, 52 patients with proven precapillary PH were included during standard echocardiographic work-up. Patients were hemodynamically stable and compensated. PH diagnosis was based on previous diagnostics including right heart catheterization. The group comprised 22 patients with pulmonary arterial hypertension (PAH), 21 patients with chronic thromboembolic PH (CTEPH) and 7 patients with interstitial lung disease-associated PH (ILD). The diagnostic algorithm was consistent with current international guidelines. Patients with left-sided heart diseases were excluded. Thirteen healthy volunteers were included as control group.All participants received standard echocardiography. Standard parameters were acquired according to international guidelines as published by the American Society of Echocardiography . As showTM software package  was used according to vendor instructions. For calculation of left ventricular rotation, 2D speckle tracking (STE) was performed at all three acquisition levels and the results were exported as raw data. Three consecutive equally spaced beats (less than 10% beat-to-beat variation of cycle length) were analyzed. The standard parameters of echocardiography were collected using a custom python script to construct a relational database for further analysis.All echocardiographic data were analyzed on an EchoPAC workstation . For RV measurement, the TomTec-ArenaData were analyzed with R statistical software package  and a p<0.05 was considered statistically significant. Scalar data were examined for normality by Kolmogorov-Smirnov-test. Data from the control subjects have a narrow distribution of EI around mean. The data have three features: a) small sample size; b) inhomogeneity of variance; and c) asymmetry of distribution. We thus opted for the Kruskal-Wallis-H-Test for scalar variables. For the more complex analysis of continuous data, which is the focus of this study, we opted for a method using permutation testing. We therefore limited confounding variables and avoid further subgroups in this dataset due to the small sample size. All results are displayed as median and range.For time dependent analysis of torsion, functional data analysis (FDA) was applied. Therefore, instantaneous net torsion angle and torsion rate were extracted and replaced by a function modeling of the data. As measurements are distributed equidistant in time, a Fourier expansion model with n = 9 basis functions was used to create a function of expected torsion and torsion rate, respectively. The cycle length T to calculate frequencies of the Fourier functions was set to 100%. Due to this functional approach, no normalization of raw data was necessary. Smooth coefficients of the expansion were estimated by minimizing the unweighted least square criterion SMSSE. This produced a single deformation pattern to each time point within the heart cycle of each patient for further analysis. To analyze the impact of left ventricular eccentricity on time dependent rotational movement, a functional linear model was fit depending on EI treated as a continuous variable. The null hypothesis was tested that rotational movements are the same regardless of EI values. Due to the functional nature of the method, theoretical distributions could not be calculated. Therefore, a permutation F-test was applied to calculate global and pointwise F-statistics. Methodological details have been published previously .The study complies with specifications from the declaration of Helsinki and was approved by the local ethics committee . Written informed consent was obtained from patients and healthy volunteers.The anthropomorphic parameters are shown in Echocardiographic examination results are shown in As shown in In patients with PH, the maximum torsion was significantly lower compared to healthy control subjects . Furthermore, the peak occurred significantly later during the heart cycle . Maximum torsion and twist rate were similar between the two groups .Analysis demonstrated a relationship between torsion and left ventricular eccentricity as resembled by EI. Figs Septal movement was analyzed using displacement at mitral valve, papillary muscle, and apical short axis views. The systolic inward movement was most prominent in the mitral valve and papillary muscle levels. In contrast, differences during diastole were only detected in the apical short axis views , mid rowUnivariate analysis demonstrated negative correlations of both maximal torsion and maximal systolic torsion rate with left ventricular septal to inferior-posterior diameter .Stroke volume correlated negatively with eccentricity of the LV . This was revealed as consequence of diminished end-systolic and end-diastolic volumes as seen in the negative correlations with EI . No correlation was found with left ventricular ejection fraction. With decreasing right ventricular ejection fraction, eccentricity of the left ventricle increased , while right ventricular or atrial end-systolic and end-diastolic volumes were not correlated with EI. Instead, the highest correlations of EI were seen with end-diastolic pulmonary artery pressure  and right ventricular systolic pressure .Eccentricity of the left ventricle was not associated with altered diastolic function of the left ventricle by univariate analysis. However, an association of left ventricle eccentricity with right ventricular filling was seen. The tricuspid A-wave was correlated with EI , while tricuspid E-wave and E/A-ratio were not correlated. In time-resolved plots of left ventricular torsion by A-wave-velocity, significantly higher systolic and diastolic torsion can be seen. Untwisting of the left ventricle was faster (highly negative torsion rate) with increasing A-wave-velocity and E/A-ratio.In this study, we demonstrated that alterations of the right ventricle due to PH affect left ventricular mechanics and specifically the left ventricular torsion and torsion rate. To the best of our knowledge, the only structured examination of these left ventricular characteristics until then has been provided by Puwanant et al. . RegardiIn this examination, net torsion was used for time resolved analysis opposed to normalized values as described in previous studies . NormaliThe analysis of septal deformation demonstrated the inhomogeneity of septal mechanics due to right ventricular pressure overload and consecutive left ventricular geometric changes. While septal displacement analysis reflects the visual impression in short axis views with main changes during systole in all parts of the septum, radial and circumferential strain showed a more complex picture. Radial strain showed no delay of peak deformation and main changes were found during systole at mitral valve level. In contrast, circumferential strain in the same area was markedly delayed and pronounced. This might support the initial hypothesis of passive fiber insufficiency due to the geometric changes of the left ventricle.Complex anatomical changes demand 4D-echocardiography for acquisition of ventricular volumes and ejection fraction. In the current investigations, we found EI to be negatively correlated with LV stroke volume. It has been published previously that in PH left ventricular volumes are diminished and associated with both reduced filling and reduced stroke volume . This isThe analysis of the right ventricle using 4D-echocardiography showed markedly increased right ventricular volumes and reduced ejection fraction in PH patients. Though, correlation with EI was weak. This contrasts previous experiments, where acute pulmonary hypertension was shown to lead to right sided dilation of the heart and septal shifting, which was resolved by pericardial fenestration . InsteadOf note, patients with PH tend to develop peripheral right bundle branch block which has been attributed to increasing fibrosis of the moderator band . This miFunctional statistics permit to evaluate where and with what level of difference between groups an event occurs along the time. In the work presented, for the first time functional statistic to evaluate left ventricular torsion and torsion rate along the different phases of the heart cycle were used. This methodology allowed for detection of differences in rotational deformation of the left ventricle in patients with pulmonary hypertension. Furthermore, it provided detailed insights into segmental time-resolved wall deformation and functional mechanics. Pulmonary hypertension is not always easy to diagnose and follow up by echocardiography. Therefore, the methodology described in here provides additional parameters that can help to follow up disease progression and response to new drugs.Regarding the acquisition of torsion rate, STE at optimized conditions was used in the current study. Temporal resolution, however, still has both an upper and a lower limit. On one hand, the minimally detectable change in location of the myocardial reflectors sets an upper limit to the frame rate. On the other hand, the lower the frame rate, the broader the time interval needed to calculate torsion rate becomes, leading to a reduction in temporal resolution. Mathematically, this becomes less important as functional statistics were used and there is only a minor impact on the parameters of the functions. Though, this might not suffice for patient to patient comparison using this technique and does not result in feasible parameters or cut-off values to use as a diagnostic tool in daily patient care.It is to note that EI is a time-varying measurement. The time variation of LV eccentricity is incompletely understood. It has been considered that volume overload could lead to D-sign in end diastole to mid systole phase, while pressure overload could lead to D-sign in mid systole to end systole phase; however, above statements are rather based on common sense without solid support from clinical/experimental data. It is known that there is an overlap between both volume and pressure overload induced maximum eccentricity, and the overlap spectrum is wide as well. King et al. described a progression of the D-sign from end-diastole to end-systole with increasing RV to LV pressure gradient . The reaThe patient sample in this study was relatively small; the obtained results thus suffer some kind of selection bias. Further studies with larger samples are warranted to confirm these findings.In the present study, advanced numeric and statistical techniques were used to investigate the influence of left ventricular eccentricity on dynamic torsion mechanics, demonstrating the effects of biventricular geometric changes due to pressure overload of the right ventricle on the torsion component of the left ventricle. Analysis of the time course of torsion or determination of the eccentricity index as single parameter might proof useful in future investigations on the interaction between left and right ventricular morphology and function.S1 Data(XLSX)Click here for additional data file.S2 Data(XLSX)Click here for additional data file.S3 Data(XLSX)Click here for additional data file.S4 Data(CSV)Click here for additional data file.S5 Data(CSV)Click here for additional data file.


Left ventricular reverse remodeling (LVRR) has been detected in non-ischemic dilated cardiomyopathy (NIDCM) patients following optimal treatment. However, its prediction with only conventional modalities is often difficult. This study sought to examine whether RNA sequencing (RNA-seq) of myocardium tissue samples could predict LVRR in NIDCM.A total of 17 advanced NIDCM patients with left ventricular ejection fraction (LVEF) below 30% who underwent cardiac biopsy from Left ventricle (LV) were prospectively recruited. They received optimal treatment and followed with echocardiogram every 6 months. Based on LVRR status after 12 months of treatment, patients were divided into the reverse remodeling (RR) or non-RR group. Tissue samples were analyzed by RNA-seq, and a functional analysis of differentially expressed genes was carried out.Nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunit (NDUF)S5 and Growth arrest and DNA-damage-inducible protein (GADD)45G, along with several genes related to the mitochondrial respiratory chain and ribosome, were significantly downregulated in the RR as compared to the non-RR group.There were eight and nine patients in the RR and non-RR groups, respectively. No difference was found in age, sex, disease duration, LV end-diastolic diameter, and LVEF between the two groups. There were 155 genes that were differentially expressed between the two groups. GADD45G and NDUFS5 are potential biomarkers for LVRR in patients with advanced NIDCM. Heart failure has a complex etiology and is associated with various conditions, and is a major cause of adult mortality. In particular, non-ischemic dilated cardiomyopathy (NIDCM)—which is characterized by left ventricular (LV) dilation and a severely reduced LV ejection fraction (LVEF) without coronary artery disease—is often refractory to established drugs such as β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers and to cardiac resynchronization therapy (CRT). Therefore, NIDCM often requires heart transplantation or ventricular assist device (VAD) implantation. However, the former is available only to a limited number of patients, whereas the latter is associated with complications like stroke, bleeding, and infection that can be fatal during the long waiting period for transplantation .On the other hand, many NIDCM patients show recovery of cardiac function after optimal pharmacological or device therapy , 3. ThisAnalyzing myocardial gene expression can be more useful for this purpose. Several studies have demonstrated a clear correlation between myocardial expression of certain mRNAs or micro (mi)RNAs and LVRR in NIDCM patients by quantitative reverse transcription PCR , 14. MorPatients with advanced NIDCM whose LVEF was < 30% by echocardiogram and who underwent cardiac biopsy of the LV at Chiba University Hospital from September 2014 to May 2016 were included in the study. Exclusion criteria were as follows: (i) heart failure with ischemic etiology ; (ii) inflammatory or infiltrative heart disease including myocarditis, sarcoidosis, or amyloidosis; (iii) other secondary or metabolic cardiomyopathies such as neuromuscular disease and alcoholic cardiomyopathy; (iv) dependence on hemodialysis; and (v) age younger than 20 years or older than 65 years.Prior to myocardial biopsy, all patients underwent blood sample collection, echocardiogram, and right heart catheterization. After myocardial biopsy, patients continued to receive optimal treatment including guideline-directed medical therapy with β-blockers and renin-angiotensin blockers and CRT. Patients were followed for 6 to 12 months, with echocardiogram performed at each follow up; they were then divided into the reverse remodeling (RR) and non-RR groups according to positive or negative LVRR status, respectively. LVRR was defined as (i) LVEF improvement of > 10% in absolute value, and (ii) LVEF > 30%.LV myocardium samples were collected at the time of cardiac catheter examination or open heart surgery, including for VAD implantation and valve replacement. Samples were immediately treated with RNAlater RNA stabilization reagent  and stored at − 20 °C. Total RNA was extracted using mirVana miRNA Isolation kit  according to the manufacturer’s instructions, and cDNA libraries were generated using a NEBNext Ultra RNA Library Prep kit . Sequencing was performed using a HiSeq1500 system  with a single-read sequencing length of 60 bp.TopHat v.1.3.2 with default parameters was used to map sequences against the UCSC/hg19 reference genome. Gene expression level was quantified using Cufflinks v.2.0.2 , 23 as fNDUFS5, 5′-gatttcgtagagtgtttgcttcg-3′ (F), 5′-gaggtggaggggtgtactttc-3′ (R), probe number #38 ; GADD45G, 5′-cagccaaagtcttgaacgtg-3′ (F), 5′-cctggatcagcgtaaaatgg-3′ (R), probe number #71 .When the same cDNAs as for RNA-seq were available, quantitative real-time PCR (qPCR) was performed on a Light Cycler 480 instrument  using the Taqman Universal Probe Library and the Light Cycler 480 Probes Master  according to the manufacturer’s instruction. 18S ribosomal RNA was used to normalize the RNA content of the samples. Obtained results were expressed as relative mRNA levels of the cycle threshold value, which was then converted to fold change. Designed primer pairs and probe number are as follows: 2 test. P < 0.05 was considered statistically significant. DEGs were defined as those with a significance (P) value < 0.05, false discovery rate < 5%, and fold change > 1.5, which was determined using the R v.3.1.0 software tag count comparison function [P < 0.05. Data were analyzed using R version 3.3.2 .For patients’ clinical data, continuous variables are expressed as the mean ± standard deviation and were compared with the unpaired t test, whereas categorical data are expressed as a percentage and were compared with the χfunction . The sigP values < 0.05 in the univariate analysis were entered into the multivariate model. A P value < 0.05 was regarded as statistically significant. Data were analyzed using STATA version 15.1 .Logistic regression analysis was used to assess the impact of selected DEGs on LVRR. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Confounders with A total of 20 patients were enrolled in this study. Two were excluded due to insufficient RNA amount and heart transplantation in the prior 6 months, respectively. One patient diagnosed with acute fulminant myocarditis was also excluded. Ultimately, 17 patients  without coronary artery disease or other secondary or specific cardiomyopathies were analyzed. LV myocardial samples were obtained by transcatheter biopsy for four patients, by needle biopsy during aortic valve replacement surgery for three patients, or during VAD implantation for 10 patients.n = 8) and non-RR (n = 9) groups based on the findings of a follow-up echocardiogram. There were no differences between the two groups in terms of age, sex, disease duration, LVEF on the echocardiogram, brain natriuretic peptide level, cardiac index for right heart catheterization, or ratio of cardioprotective medications 5, and Growth arrest and DNA-damage-inducible protein (GADD)45G  as well as various ribosomal proteins were also upregulated. ROC curve analysis revealed that the three genes  had high predictive capacity for LVRR , 14,448 genes were retained for analysis. Of these, 155 were differentially expressed between the RR and non-RR groups, with 150 genes upregulated in the non-RR group . In multivariate analysis, neither of these variables showed significant correlation with LVRR, with GADD45G demonstrating borderline significance .Logistic regression analysis was performed to examine the influence of clinical variables including selected DEGs on LVRR Table . In univLOC100506295, NDUFS5 along with those encoding other NDUF subunits, GADD45G, and some genes encoding ribosomal protein subunits were upregulated in the non-RR as compared to the RR group; and (ii) genes associated with the mitochondrial respiratory chain and ribosome were enriched in the non-RR relative to the RR group.In the present study, we performed RNA-seq of myocardium tissue samples from patients with advanced NIDCM and compared the gene expression profiles of those with and without LVRR. Clinically, patients with LVRR showed markedly better renal function. They also needed significantly less inotrope support, surgical biopsy and VAD implantation through shorter disease duration than those without LVRR. The major findings were that (i) several genes including LOC100506295 whose function is unknown, NDUFS5 was most highly correlated with LVRR. NDUFS5 encodes a subunit of mitochondrial respiratory chain complex I [NDUFS5 along with other NDUF subunits of mitochondria complex I play a crucial role in the pathophysiology of heart failure. This is supported by the difference in NDUFS5 expression between the RR and non-RR groups as well as the enrichment of genes related to mitochondrial respiratory chain observed in the present study. Thus, NDUFS5 and mitochondrial complex I subunits may serve as predictive biomarkers for LVRR.Other than omplex I . Previouomplex I , which iomplex I . Decreasomplex I –35, whicomplex I . These oInborn mitochondrial abnormality, i.e. mitochondrial disease (MD), can involve myocardium and induce cardiac dysfunction through disrupted mitochondrial respiratory chain functions . In addiGADD45G was found to be strongly correlated with LVRR. GADD45G is a member of the GADD45 family of proteins that are involved in p38 mitogen-activated protein kinase-dependent cell death [GADD45G overexpression in mice induced cardiomyocyte apoptosis, fibrosis, LV dysfunction, and heart failure, whereas GADD45G deletion conferred resistance to ischemic injury and cardiomyocyte apoptosis [GADD45G was more highly expressed in non-RR as compared to RR patients, suggesting that GADD45G upregulation is linked to induction of apoptosis and consequently, a reduced probability of LVRR.Apoptosis is another hallmark of mitochondrial function, with mitochondrial permeability transition pore opening to trigger intrinsic apoptosis pathway. Thus, disruption of mitochondrial function can enhance cardiomyocyte apoptosis, leading to progression of heart failure , 41. In ll death . Recent poptosis . In our Our study had two novel findings as compared to previous transcriptomic analyses of LVRR. First, we identified markers for predicting LVRR by comprehensive transcriptome analysis of single samples obtained prior to treatment. Some studies showed associations between certain mRNAs or miRNAs and myocardial recovery or subsequent VAD removal after LVAD implantation , 14, 44.Secondly, cardiac biopsy can reveal not only histological abnormalities but also the potential reversibility of cardiac function, which increases its clinical utility for NIDCM. Cardiac biopsy—particularly by the transcatheter method—is associated with risks such as perforation or idiopathic valvular regurgitation, which has thus far limited the diagnostic yield. However, taking into consideration information on the reversibility of cardiac function in NIDCM can facilitate clinical decision-making based on biopsy samples. Favorable expressions of the specific genes possibly make us advance aggressive medical treatment to avoid VAD implantation, or even to introduce VAD as a bridge to recovery strategy. By contrast, unfavorable expressions would lead us to prompt introduction of VAD as a bridge to transplant strategy.GADD45G demonstrated almost significant predictive value for LVRR in the multivariate model, which highlights the strong contribution of the gene. Reconfirmation of the results with more large samples is needed to show clinically definite significance of NDUFS5 and GADD45G. Third, there were unequal number of females and males. Some transcripts might be expressed in a gender specific manner and serve as a bias for the results of the present study. Large-scale and preferably randomized control study is required to resolve this issue. Fourth, adopted treatment strategy differed between the groups. There were more LVAD implantation in the non-RR group, however, this difference was not arbitrary and resulted from the continuing optimal treatment for severe heart failure. Mechanical ventricular support is the most potent cardiac unloading therapy and is thus likely to promote LVRR more efficiently. Nonetheless most patients with LVRR implantation fell upon the non-RR group in the present study, underscoring that the non-RR group actually had little chance to recover cardiac function even after maximal heart failure treatment. Of note, gene expression analyses were performed on the samples prior to LVAD implantation and were not influenced by the difference in the treatment strategy. Fifth, we identified LVRR only by echocardiography in both VAD and non-VAD patients, in contrast to previous studies that defined LV recovery as removal of VAD in VAD-patients [The present study had several limitations. First, this study was carried out at a single institution with a small number of samples. Previous studies examining myocardial samples from severely failing hearts could collect only around 10 samples for each treatment group , 20, 44.patients . In the NDUFS5 and GADD45G are potential biomarkers for predicting whether patients will develop LVRR, which can inform clinical decision making regarding VAD implantation and/or removal. These findings add value to conventional cardiac biopsy and can potentially improve the treatment of heart failure patients.In conclusion, we identified novel genes that are correlated with LVRR by RNA-seq in myocardium tissue samples from patients with advanced NIDCM.


Estimation of the time constant of isovolumetric relaxation - or Tau constant - is the best and most established parameter for ventricular diastolic function analysis. However, this measure is obtained through an invasive assessment and it is very difficult to acquire.5 However, the classification of the degree of diastolic dysfunction and its application in the therapeutic management of valvular heart disease remains controversial.4 Moreover, aortic stenosis may be associated with mitral annulus calcification, which may lead to a reduction of the mitral orifice area, with an increase in early transmitral diastolic velocity (E), while the Doppler lateral mitral annulus velocity (e’) may be reduced due to limitation of the posterior cusp excursion, which may lead to an artificial increase in the E/e’ ratio. In aortic regurgitation, however, the aortic reflux jet may interfere with the mitral flow, which, when significant, can lead to a restrictive ventricular filling pattern; however, the accuracy of E/e’ ratio is questionable.5The latest recommendations for diastolic dysfunction assessment by echocardiography basically include analysis of the left ventricle without structural changes and preserved ejection fraction, as well as a flowchart for cases of left ventricular ejection fraction reduction/structural change.6 The study population consists of three groups according to hemodynamic stress: aortic stenosis (significant afterload increase), aortic regurgitation (consistent preload increase), both valvopathies compared with a healthy group. Both valvopathies comprised a comparative group with the controls. This study demonstrated that the LV longitudinal movement analysis was reduced in patients with aortic valve disease when compared to the control group, and that among patients with valvular disease, patients with aortic regurgitation had lower values than those with stenosis.The present study proposes the analysis of diastolic function by analyzing left ventricular (LV) longitudinal movement, quantified by cardiac magnetic resonance imaging (cMRI).7 It is in this context that the elegant study by Ribeiro et al.6 is located and has its greatest strength: in the cost-benefit of four variables obtained simply and quickly in the four-chamber view for indirect evaluation of diastolic dysfunction, without the need for additional specific sequences or the use of specific software. However, before proposing the incorporation of this technique into clinical routine, some important methodological considerations are necessary. We know that the ventricular longitudinal shortening measured by cMRI is classically related to ventricular systolic function and, more recently, also to diastolic dysfunction measured by echocardiography, even in patients with preserved ejection fraction.10The cMRI is an attractive imaging modality capable of providing morphological, functional, perfusion and tissue characterization data in a single examination, with irrefutable spatial resolution. In the evaluation of diastolic function, recent techniques have shown encouraging results, especially those based on the myocardial strain assessment through feature tracking. However, the need for improvements in image postprocessing and acquisition times, together with the limited availability and relatively high cost of the employed software, limit a broader use of these relatively new technologies in clinical practice.10 Although the authors assumed this fact as an important limitation of the study, this absence makes it impossible to estimate the accuracy, sensitivity, specificity and predictive values of this methodology. Furthermore, the lack of interobserver agreement assessment and internal and external validation, associated with the fact that the case group consisted of a very heterogeneous population , require that these results be interpreted with extreme caution and cannot be extrapolated to other samples or distinct cardiomyopathies before being clinically validated. Other relevant data is consensually accepted that patients with severe aortic valve disease, either stenosis or regurgitation, already showing morphological alteration and ventricular compliance, are symptomatic. Patients with advanced aortic valvopathy have higher ventricular mass and reduced ejection fraction, when compared with the healthy group. In this context, measures of systolic and diastolic function can be expected to differ from those of the healthy control group.However, the authors did not directly correlate the ventricular longitudinal movement variables with Doppler echocardiographic variables, data with broad and widespread importance in the noninvasive investigation of diastolic dysfunction, or with invasive variables to validate these measurements.As a suggestion for future studies, the inclusion of other variables, easily obtained in the basic cMRI sequences, such as left atrial volume (a chronic marker of diastolic dysfunction and cardiovascular risk) or the presence of late LV enhancement  would certainly add important data to the debate on the role of cMRI in LV diastolic dysfunction. Moreover, it would be interesting to perform its validation with methods that are clinically used as invasive measures of the Tau constant, or through echocardiography parameters, which are validated measures for the analysis of diastolic function in different heart diseases.


TM (Boston Sci.). The Fourier Transform was used to identify the spectral content of the first six seconds of signals recorded in the RV and LV simultaneously. In addition, measurements that were based on Information Theory were scrutinized, including Entropy and Mutual Information. The results showed that in most patients the spectral envelopes of the EGM sources of RV and LV were complex, different, and with several frequency peaks. In addition, the Dominant Frequency (DF) in the LV was higher than in the RV, while the Organization Index (OI) had the opposite trend. The entropy measurements were more regular in the RV than in the LV, thus supporting the spectral findings. We can conclude that basic stochastic processing techniques should be scrutinized with caution and from basic to elaborated techniques, but they can provide us with useful information on the biosignals from both ventricles during VF.Ventricular fibrillation (VF) signals are characterized by highly volatile and erratic electrical impulses, the analysis of which is difficult given the complex behavior of the heart rhythms in the left (LV) and right ventricles (RV), as sometimes shown in intracardiac recorded Electrograms (EGM). However, there are few studies that analyze VF in humans according to the simultaneous behavior of heart signals in the two ventricles. The objective of this work was to perform a spectral and a non-linear analysis of the recordings of 22 patients with Congestive Heart Failure (CHF) and clinical indication for a cardiac resynchronization device, simultaneously obtained in LV and RV during induced VF in patients with a Biventricular Implantable Cardioverter Defibrillator (BICD) Contak Renewal IV Cardiovascular diseases are currently the leading cause of death worldwide. The World Health Organization (WHO) estimates that, in 2012, approximately 17.5 million people passed due to these diseases, and it is estimated that by 2030 almost 23.6 million people will pass from some cardiovascular disease, with the coronary heart disease  being the most common cause [The search of successful therapies for the prevention of sudden cardiac death has motivated the development of studies focused on the ventricular signal analysis during VF, in order to better understand the mechanisms underlying its apparently chaotic behavior. During the second half of the 20th century, the predominant hypothesis to understand the VF mechanisms was based on the random and disorganized propagation of multiple waves ,5. HowevTM (Boston).Currently, VF is medically treated with resynchronization devices, known as implantable cardioverter defibrillators. These devices are suitable for research purposes, as they allow the simultaneous and accurate recording of the electrograms (EGMs) of RV and LV during a VF event . Based oThe intracardiac EGM signals of both ventricles were compared in terms of their spectral content and their shared information and, for this purpose, we used basic representations of the frequency spectrum, as well as the fundamental calculations of the Shannon entropy and MI in said signals. The contributions of the paper are twofold. First, the knowledge of fundamental information about the VF mechanism is scrutinized in human VF, which represents a scenario where much is still unknown. Second, the consistency of spectral and Information-Theory based measurements is also analyzed, which has been rarely addressed in the VF analysis literature.This document is organized as follows. The study of human electrophysiological signals has been the subject of special research interest. The intracardiac signals are not an exception, since one of the frequent causes of death in the world is heart diseases, such as the arrhythmias caused by VF events. For this reason, there are several studies that are focused on finding successful therapies for the prevention of sudden cardiac death. In this section, different research works are addressed, which were oriented to the application of spectral content study techniques as well as to non-linear analysis of electrophysiological signals.The spectral analysis of cardiac signals has made possible to identify, in detail, the content of the harmonics of the cardiac rhythm when present, and from this, the periodic components included in the signal as peaks of the power spectrum have been quantified . In thisNonlinear analysis methods are being increasingly used in the study of cardiac biopotentials, especially in cases, such as arrhythmias, whose signals are characterized by nonlinear and nonoscillatory spectral components, conditions that can be similar to those of some nonlinear dynamic systems ,23. SeveThe above presented background shows that the research developed on the spectral and nonlinear analysis of VF waves is comprehensive, and it has improved our knowledge on aspects, such as the initiation mechanisms , the acuCurrently, VF is treated medically with resynchronization devices known as internal cardiac defibrillators. The function of this device is to place electrodes in the internal heart chambers which capture several bioelectric signal. These defibrillators are placed in patients with CHF, and in addition to their resynchronization role, they are also capable of detecting cardiac arrhythmias and recognizing when VF is involved, while accurately recording the EGM of RV and LV during VF in humans .P wave, QRS complex and T wave, as illustrated in P wave and the QRS complex is called the depolarization wave, because the P section represents the electrical potentials that appear when the atria are depolarized before their contraction, while the QRS complex represents the electrical potentials that are generated when the ventricles are depolarized before their contraction. The T wave section, on the other hand, is known as the repolarization wave, since it represents the electrical potentials generated when the ventricles recover from the depolarization state, also known as repolarization [P-QRS-T waves can be modified by the presence of some serious cardiac pathology, such as VF, which can be defined as a spontaneous and asynchronous and local contraction of cardiac muscle fibers that prevents the effective and global ventricular contraction. This causes blood pressure to drop rapidly, which interrupts the blood supply to vital organs. P-QRS-T pattern, which is completely absent. In these circumstances, the heart rate is extremely irregular, producing uncoordinated electrical activity of the heart that can cause death within seconds [Heartbeats are caused by electrical impulses as a result of exchanging ions such as sodium, potassium, or calcium, among others. The electrical impulses propagate through the heart tissues, thereby generating small currents on the cardiac cells and fibers . This berization . The mor seconds .reentry, which would be given here by the helical and unbroken circulation of electrical impulses, either anatomical or functional. These impulses would rotate following dynamics determined by an organizational pivot, they are commonly called rotors, and they generate waves with excessively high component frequencies as compared with the sinusal rhythm, so that ineffective cardiac contractions are provoked. The rotors behave as rotation centers that produce multiple electrical activation fronts at some distance from them, and they are conditioned by the myocardial electrophysiological properties, which, in turn, depend on the different ionic current dynamics. Early research revealed that rotors play a significant role as VF producing agents in both animal and human models [The VF is the main cause of sudden cardiac death and, unlike of other arrhythmias, it is considered to be pharmacologically unapproachable, since it seems a succession of uncoordinated and chaotic electric fronts. During several decades, the VF prevention strategies have principally focused on the suppression of the ectopic ventricular beats, which could even precipitate the disease. However, the clinical results reported in the literature have not contributed significantly to the reduction of this cardiac condition ,39,40,41n models ,45,46. HTM from Boston Cientific Corporation. The CRT uses isolated electrocatheters connected to the device and implanted in the heart. The wire transmits the signal from the heart to the device, and then it carries the energy from the device to the heart to coordinate its rhythm [This study was performed on patients with CHF problems using the same equipment to take data from the detection of VF. The equipment used to measure the signals from the ventricles is known as Cardiac Resynchronization Therapy (CRT) device; it senses the heart signals from the two ventricles and, when necessary, it delivers an electrical shock to the heart to restore the extremely fast and sometimes irregular heart rhythm to a normal rhythm. CRT devices convey a small computer powered by an internal battery, securely sealed inside the box. The device continuously monitors the heart rhythm by recording information and it provides electrical therapy to the heart when it detects an arrhythmia. Several device types have been developed, including pacemakers (CRT-P) and defibrillators (CRT-D). In this research, we used the CRT-D device model Contak Renewal IVs rhythm .The device has five electrical connectors arranged, as follows: two defibrillation output connectors with DF-1 connector generate electrical shocks that are located in the RV; three sensor input connectors are connected to the RV with IS-1 connector, to the LV with LV-1 connector, and the third is connected to the Right Atrium (RA) with an IS-1 connector. The medical procedure applied by professionals in the field indicates that the sensor cable connection goes to the LV, the defibrillation and sensor cables are connected to the RV, and the sensor cable going to the RA remains disconnected at all times ,49, as sFor data acquisition, two types of electrodes were used with Contak Renewal IV, which were the Easytrak 2 model  . The samDuring the implant procedure in patients, electric shocks were delivered to the ventricles generating a controlled VF episode in order to test the device functionality, and these signals were recoreded through the sensors. Two tests were performed in most patients, but only the first recording was included in the study to avoid possible differences due to consecutive shocks. We also recorded demographic data (age and sex), heart disease , drugs at the time of implantation, echocardiographic parameters, and implantation data (including minimum energy and number of shocks for successful defibrillation).Biomedical signals in time are the result of biopotentials changing in the spatial and in the temporal domains. However, in some cases it is desirable to study them in the frequency domain, both in deterministic and in stochastic problem statements. Frequency analysis can be performed while using representations based on the Fourier Transform of a given signal, for instance, for the LV recorded signal in a patient, we have thatFrom the Fourier Transform, we can measure parameters that have been previously proposed in the literature, such as the Fundamental Frequency (FF) , the Domplitudes , as show its 75% . The Org its 75% ,54. The  its 75% .For our research, we used the periodogram proposed by Welch, which consists of dividing the time signal into overlapping segments at 50%, finding the Fourier Transform for each segment, and averaging the estimated windowed spectral densities. The averaging in the periodgram tends to reduce the estimator variance over the entire time series. On the other hand, although the overlap between consecutive segments introduces redundant information, this effect can be minimized by the use of non-rectangular windows that reduce the importance or weight given to the final samples of the segment . SpectraInformation Theory is the mathematical treatment of the concepts, parameters, and rules governing the transmission of messages through communication systems. It was founded by Claude Shannon toward the middle of the twentieth century and has since then evolved into a vigorous branch of mathematics, while fostering the development of other scientific fields, such as statistics, biology, behavioral science, neuroscience, or statistical mechanics. The techniques used in Information Theory are probabilistic in nature, so that some authors see Information Theory as a branch of probability theory ,57. The The entropy is conceptualized in general terms as a natural trend measure of the order loss or peculiarity of certain combinations, and it is a widely used concept in fields, such as thermodynamics, statistical mechanics, and astrophysics, among others. In the Information Theory field, the entropy  is a measure of the uncertainty degree that exists on a data set generated from a random experiment, as well as the necessary information to limit, reduce, or eliminate this uncertainty in any stochastic process. The Shannon entropy is also defined as the average rate at which the information is produced by a stochastic data source, and for a stochastic process , several practical considerations need to be taken into account. The algorithmic implementation can be obtained by any interested reader under mail request.n = 3) or NYHA III (n = 15) status. Four patients were on amiodarone treatment.Twenty-two patients  had dilated cardiomyopathy  in NYHA II  are performed, which would modify the clinical management. It also can be seen (not shown) that spectra among different patients can noticeably differ. However, the consistency of the spectral parameters points out to the underlying bioelectrical processes being not too complex in some sense from the spectral point of view. The basic periodicity structure is in general well captured by the set of a fundamental frequency, its harmonics, and the spectral envelope , whereas the fluctuations from this periodicity are captured by the bandwidth, the organization, and the LK parameters. The significance of parameters mostly holds from the first three seconds to the next three seconds. Whereas, the spectral envelope has relevant differences, the DF would represent an inconsistent parameter, as it depends on the envelope (it could correspond to different harmonics in different patients), but the fundamental frequency is the basis for the near-to-periodic structure of the signals that can be recognized. Note that the configuration of sensing electrodes could be a confounding factor on the spectral envelope, but parameters as FF and organization measurements should be less dependent from spectral envelope signatures due to different electrode configurations.N. We found that the choice of these parameters in the literature often is presented as heuristically tuned, whereas their choice can have a definitive impact on the final accuracy and quality of the parameter estimations.The parameters calculated from Information Theory principles are usually obtained by discretizing the equations presented in We performed a set of simple experiments to previously check that the free parameter setting was adequate in order to estimate the entropy of each of two processes, their joint entropy, and their MI. For this purpose, we generated a bivariate Gaussian process with zero mean and covariance matrix, given byN, between N large enough, we obtain good quality estimation for alll or the parameters and for almost any bin size. For a moderate number of available samples, it is still possible to obtain good quality estimators as far as the bin size is not too small, whereas for a low number of available samples there will be an unavoidable and uncontrolled bias on the estimators.A different run of values was generated for each value of N, but we can still scrutinize the effect of changing the bin size on the estimated parameters and scrutinize whether said estimation reaches a stable point, so that we are either in the middle region of this kind of graph or we are in a biased region. This information will be useful to determine the adequate bin size on these estimators.In a real case, we will have to work with a fixed number of samples N for each signal is previously fixed in real recordings, so we used all of the available samples for each signal, and we swept the bin width A second experiment was performed to measure the MI in the analysis of cardiac signals to scrutinize the relationship between recordings in each ventricle for each patient. The number of samples According to the behavior observed in the Information-Theory based measurements on the synthetic data experiments, we should chose a bin width as large as possible without introducing distortion, and given the strong presence of bias due to the moderate number of available time samples, we choose the same bin width for all the signals, aiming to control this bias for this population. We checked several bin widths , and the populational behavior was similar in them. As it can be seen in t-test). This seems to be consistent with the existence of more complex bioelectric activation in the LV as compared with the RV, although the differences in the configuration of the electrodes is again a possible confounding factor that should be taken into account. Note that the Joint Entropy is conformed to be a slightly smoothed version of the combination of both entropies, but not just their summation, and that the MI is, in general, weakly correlated with any of the previous components. This indicates that Entropy, Joint Entropy, and MI are measuring different aspects or the information content in these signals.In this work, we have presented a spectral and a non-linear analysis of the LV and RV signals simultaneously acquired during induced VF in 22 patients with CHF and clinical indication for a BICD. During the induced VF in the implant procedure, the EGM obtained between the tip and ring of the RV electrodes and the EGM of the bipolar epicardial electrode in the LV were recorded. The Fourier representation of the first six seconds of the signals recorded for RV and LV made it possible to identify spectral parameters, whereas the Information Theory content both in individual and grouped recorded signals was scrutinized using Shannon entropy and MI. Our analysis showed that VF spectra were complex and several frequency peaks were observed in most patients, showing a DF that was greater than the LV than in the RV, while the OI had the opposite trend. With respect to the entropy and MI study, we concluded that, in all cases, the reduction in the bin size of the histogram improved the association between the RV and LV signals, as evidenced by the progressive increase in Entropy and MI until maintained value approximately constant and independent of that continue reduction of the histogram bin size. When accounting for these aspects on the estimators in Information Theory parameters, the LV was checked to be more variable in terms of Entropy, whereas the RV was checked to be smoother, on a trend which was consistent for all the patients.After early interest of studies in VF on advanced Information-Theory based measurements, they have not received so much later attention as the spectral-based measurements. In this work we have scrutinized basic entropy-related measurements, and they have proved to be informative in this scenario. However, a word of caution should be kept, as far as the simple consistency check performed in our work is often lost in the literature. We have seen that the number of samples is bringing variance and bias in the real signals, which is in accordance with the sensitivity analysis on synthetic signals for the number of samples and the bin size. Other methods could be used to improve the consistency of these kind of indices, for instance, the use of Parzen window estimators for deriving the entropy could be reducing bias and variance. Therefore, it seems recommendable to use several types of features, including temporal, spectral, and entropy-based characteristics for VF signals, in order to give a wider view of the underlying dynamics.The measurements obtained herein showed significant differences in the spectral characteristics of the electrical signal from the RV and LV as recorded by the electrodes of a biventricular resynchronization device during induced VF. Specifically, the DF was higher in LV, whereas the organization was higher in the RV. A different pattern of the ventricular activation signal in RV and LV has been reported in experimental settings. In a swine model of induced VF with epicardial recordings, Rogers et al.  found leThe DF of VF bioelectric recordings has been shown to be higher in the LV than in the RV in some experimental models, thus suggesting that discrete, high frequency, and relatively organized sources of electrical activation in the LV may be responsible for the maintenance of the arrhythmia, being the RV a bystander. Very few data are available on the literature to know whether this hypothesis can be extrapolated to humans. Our study provides data from patients with VF and suggests that the arrhythmia mechanisms may be similar to those ones described in experimental models. Some consequences of this conclusion are that potential approaches to prevent VF using ablative techniques, as well as new techniques for effective defibrillation, should focus on the left ventricle. Furthermore, the informative parameters can be easily obtained in the available resynchronization devices, and their analysis might help in the distinction between VF and other irregular rhythms with high ventricular rate, such as atrial fibrillation, or even noise due to an electrode dysfunction, often being erroneously interpreted as VF by contemporary devices.The present problem represents an scenario where acquiring, digitizing, and analyzing bioelectric signals can be useful for compiling basic knowledge on a relevant scenario (VF mechanism elucidation for subsequently elaborating new therapies for it). However, the sensors available in an informative group of patients (CRT devices) have been designed for another purpose (resynchronization sensing and therapy), which should be preserved. The point raised in the sensors arena is whether it still can be possible to obtain reliable and informative measurements with respect to the dynamics of this arrhythmia in each ventricle despite each ventricle has a different sensor signature for signal acquisition. In this case, the solution that we can reach comes from using a diversity of measurement principles  and a diversity of parameters (near-periodicity and its fluctuations).The main limitation of the present study is the limited availability of recordings in the LV and RV, which precludes a more accurate estimation of the activation characteristics in both chambers. Moreover, the signals had to be recorded with different electrodes and from epicardium in the LV versus the endocardium in the RV, hence introducing possible confounding factors in the results. These limitations are intrinsic to the recording procedure, and we aimed to compensate for it to some extent by using measurements of different nature, namely, spectral and Information-Theory based measurements, which exhibited consistent results between themselves. Although the nature of the EGM lead configurations is sometimes obviated in studies in implantable devices, our study indicates that the effect of lead configuration can have a highly relevant effect on the periodicity and organization indices when using spectral measurements. Finally, the results apply to episodes of VF that are induced from the RV apex, but might not extrapolate to the spontaneous episodes or to other induction methods. From the clinical point of view, the DF has been related to the defibrillation threshold, ,69 and tWe conclude that signal processing techniques based on spectral-analysis and entropy-based features in intracardiac recordings can be useful for analyzing the underlying dynamics of VF, which today and after years of intense research, remains unknown. Caution should be taken with Information-Theory measurements and the bias and variance properties of their estimators, but they can then provide useful information. Differences are obtained between the nature of the signals in the RV and in the LV, and though the sensing configuration could be a confusing factor, still these differences seem consistent across parameters of different kinds in stochastic processing.