Left ventricular myocardial remodeling could play an important role in the progression of chronic heart failure (CHF) syndrome in dogs with mitral valve endocardiosis. The aim of this study was to evaluate the left ventricular myocardial remodeling in dogs with mitral valve endocardiosis and to study the dependence of the incidence of this pathological phenomenon on the functional class (FC) of progression of the CHF syndrome.A total of 108 afflicted dogs and 36 clinically healthy dogs were examined using transthoracic echocardiography. The following structural and geometric parameters of the left ventricular remodeling were evaluated: Myocardial mass and its index, sphericity index at the end of systole and diastole, end-systolic and end-diastolic relative wall thickness, and integral remodeling index.In all clinically healthy dogs, a normal type of the left ventricular chamber geometry was revealed, whereas, in dogs with mitral valve endocardiosis, the normal geometry of the left ventricle occurred in 56.4%, eccentric hypertrophy in 24.1%, concentric remodeling in 10.2%, and concentric hypertrophy in 9.3% of the cases. In patients with endocardiosis, there was no dilatation type of cardiac remodeling observed.When compared to the clinically healthy animals, the dogs with mitral valve endocardiosis presented with indicators of structural and geometric remodeling, such as increased myocardial mass, myocardial mass index, and sphericity index at the end of systole and diastole, as well as relatively reduced integral systolic index of remodeling and systolic relative thickness of the walls of the heart. The parameters of the left ventricular myocardial remodeling correlated significantly with the FC of CHF syndrome. Hereditary and acquired pathologies in animals of both non-infectious and contagious etiology are very diverse and complex, characterized by various forms of manifestations, which are often difficult to diagnose and require special approaches in treatment and prevention -6.Endocardiosis of the mitral valve is caused by its myxomatous degeneration, and it is the most common among acquired heart diseases in dogs. The prevalence of this pathology is about 14-40% in the population of small breed dogs ,7,8. EndBased on the potential adverse outcomes and high prevalence of endocardiosis in dogs, its accurate and early diagnosis, and effective monitoring of the progression of CHF, it is a major problem in the veterinary medicine involving small domestic animals. Standard transthoracic echocardiography in dogs is currently regarded as a non-invasive diagnostic method for early detection of mitral valve lesions that assess the severity of mitral regurgitation as well as its effect on cardiac remodeling, left ventricular myocardial function, and indirect determination of pressure in the pulmonary artery ,14,15.The processes of the left ventricular remodeling in dogs with mitral valve endocardiosis begin in the preclinical stage and reach maximum changes in severe CHF -18. HearThe clinical diagnosis of the left ventricular myocardial remodeling in animals and humans is based on identifying its morphological changes, especially the changes in cavity diameter, mass (hypertrophy and atrophy), and geometry  using echocardiography or magnetic resonance imaging ,23,24.According to modern views on the neurohumoral mechanisms of the development of CHF, in addition to the activation of the sympathetic-adrenal system, the renin-angiotensin-aldosterone system, endothelial dysfunction, activation of inflammatory processes, oxidative stress, and endothelial dysfunction should be referred. These pathological processes stimulate the processes of remodeling, impairing hemodynamics, and retention of sodium and water in the bodies of humans and animals with CHF ,22,25,26Therefore, the study of patterns of the left ventricular remodeling in dogs with acquired valvular atrioventricular valve defects is relevant and can serve as a theoretical basis to develop effective methods that predict the effects of these pathologies and methods for early pathogenetic therapy.The aim of this study was to evaluate the left ventricular myocardial remodeling in dogs with mitral valve endocardiosis and to study the dependence of the incidence of this pathological phenomenon on the functional class (FC) of progression of the CHF syndrome.This study was performed in accordance with the Bioethical committee guidelines, and all the procedures were carried out pursuant to the Russian legislation on animal care and the European Guidelines on Animal Welfare. Owners’ informed consent were obtained for treatment and for the use of the data for research purposes.This study was performed from 2017 to 2019 on the basis of the Veterinary Medicine departments of MGUPP and RUDN Universities in the Veterinary Clinic of the Institute of Veterinary Medicine, Veterinary Sanitary Expertise and Agro-Security of Moscow State University of Food Production  and the Center of Veterinary Innovative Medicine (VIC) of the RUDN University , private veterinary clinic “Avettura” , private veterinary clinic “Epiona” . It included dogs of small breeds afflicted with mitral valve endocardiosis (n=108), with body weight 4-19 kg (8.3±0.26) and aged 6-13 years (8.9±0.33). As a control group, clinically healthy dogs of small breeds (n=36), with body weight 3-17 kg (9.4±0.69) and age 7-12 years (8.7±0.85), were included in the study. Animals in groups were recruited as they arrived at the clinic.The diagnosis of endocardiosis of the mitral valve in dogs was made comprehensively considering the data of anamnesis, clinical research methods, echocardiography, electrocardiography, and thoracic radiography . The staThe FCs of CHF syndrome were evaluated based on the modified criterion of the New York Heart Association .The criteria for the inclusion of dogs in the study included the presence of endocardiosis of the left atrioventricular valve with mitral regurgitation, complicated by CHF syndrome of different FCs.The exclusion criteria were the presence of arterial hypertension (systolic blood pressure >180 mmHg), infective endocarditis, open arterial duct, dirofilariasis, cancer, hypothyroidism, chronic kidney disease, acute gastric dilatation, dilated cardiomyopathy, or incomplete clinic instrumental data.Structural and geometric parameters of the left ventricle were assessed by performing an echocardiographic study in the B- and M-modes using standardized right and left parasternal positions along the long and short axes in the third to fifth intercostal space . The stuIn the apical four-chamber view of the sectoral scan mode, the relative myocardial thickness of the left ventricle in systole (RMTs) and diastole (RMTd) was determined. The RMTs and RMTd were calculated as the ratio of the sum of the thickness of the free wall and interventricular septum at the end of systole and diastole, respectively, to the end-systolic or end-diastolic dimension of the left ventricle ,19.The end-systolic and end-diastolic dimensions of the left ventricle along the long and short axes were measured. The global sphericity indices (GSI) of the left ventricular chamber at the end of systole gonadosomatic indices (GSIs) and GSI diastole (GSId) were calculated as the ratio of the end-systolic and end-diastolic camera along the short and long axes, respectively ,28.th edition” [The left ventricular mass (LVM) and the integral systolic remodeling index (ISRI) were calculated using Equations 3) and (7) [ and (7) edition” .where S is the surface area of the body; LVFWT is the left ventricular free wall thickness in systole; LVFWTd is the left ventricular free wall thickness in diastole; IVSTs is the interventricular septum thickness in systole; IVSTd is the interventricular septum thickness in diastole; RMTd is the relative thickness of the walls of the left ventricle in diastole; RMTs is the relative thickness of the walls of the left ventricle in systole; LVESD is the left ventricular end-systolic dimension; LVEDD is the left ventricular end-diastolic dimension; LVEF is the left ventricular ejection fraction; Ls is the long axis of the left ventricle in systole; and Ld is the long axis of the left ventricle in diastole.et al. [The criteria according to Ganau et al.  were useNormal geometry of the left ventricle .Dilatation type .Concentric remodeling .Concentric hypertrophy (increase in LVMMI and RMTd).Eccentric hypertrophy .The non-parametric Mann-Whitney U-test was used to compare the two groups, while the Kruskal–Wallis test was used to compare several groups. To compare the groups according to the frequency of occurrence of qualitative traits, the Chi-square criterion was used, and where necessary, the Yeats amendment was used. The relationship between the different FCs of CHF and left ventricular myocardial remodeling indices was established by the Spearman correlation method. The difference between groups of animals was considered significant if p<0.05. All calculations were performed on a personal computer using the statistical program STATISTICA 7.0 .The study included 144 dogs, of which 36 (25.0%), 37 (25.7%), 24 (16.7%), 36 (25.0%), and 11 (7.6%) animals were at Stages A, B1, B2, C, and D (ACVIM classification) of the pathology development, respectively.Echocardiographic parameters characterizing the processes of remodeling of the myocardium of the left ventricle in dogs with mitral valve endocardiosis complicated by CHF syndrome of different FCs are listed in Changes in LVM in the endocardiosis afflicted dogs complicated by CHF of various FCs were found to be true as per the calculation of the Kruskal–Wallis analysis of variance . It was established that although the LVM during development of I FC of CHF syndrome did not differ from that of the control group, but it significantly increased (p<0.001) by 1.25, 1.31, and 1.62 times in the II, III, and IV FCs, respectively. In addition, LVM in sick dogs significantly correlated with the FCs of CHF syndrome .Similarly, there were changes relative to LVMMI in endocardial dogs. The Kruskal–Wallis analysis revealed the presence of a significant difference in LVMMI between the animals of both groups . In dogs with endocardiosis, the LVMMI values significantly increased by 1.42 , 1.33 , and 1.57  times with the development of CHF in the II, III, and IV FCs, respectively.It is also necessary to add that the LVMMI reliably correlated with FCs of the CHF syndrome .In patients with endocardiosis of the mitral valve, the GSIs and GSId significantly differed (p<0.001) in both animal groups . With the development of III and IV FCs of the CHF syndrome in sick dogs, the indicators of GSIs and GSId increased significantly (p<0.001) when compared to clinically healthy dogs. It should be noted that these indices of the left ventricular myocardial remodeling significantly correlated with FCs of CHF .In patients with endocardiosis, the RMTd was not significantly different in both groups. However, the RMTs value significantly changed in animals of the different FCs of CHF . In sick animals, RMTs ranged from 0.68 to 1.74 condition units with the development of II, III, and IV FCs of CHF showing averages of 1.5±0.03; 1.2±0.04, and 0.9±0.04 conditions units, respectively, and were significantly different (p<0.05) from that of clinically healthy dogs.σ) for LVMMI (76-168 g/m2) and RMTd (0.47-0.83 relative units).The ISRI index in dogs with mitral valve endocardiosis was found to be highly informative. Thus, the value of this parameter significantly decreased with the progression of CHF . Thus, in dogs with endocardiosis complicated by III and IV FCs of CHF, the value of this indicator was significantly reduced when compared to clinically healthy dogs. There was a negative correlation of ISRI in patients with FCs of CHF . In the next stage, the type of the left ventricular remodeling in dogs with mitral valve endocardiosis using echocardiographic parameters of LVMMI and RMTd was noted . Since tAll clinically healthy dogs revealed a normal type of the left ventricular chamber geometry . It shouIn dogs with mitral valve endocardiosis, the normal type of left ventricular geometry was significantly less common. The main type of left ventricular myocardial remodeling in such dogs was eccentric hypertrophy. Thus, these types of structural and geometric changes in the left ventricular myocardium in dogs with endocardiosis complicated by CHF syndrome of II, III, and IV FCs occurred with a frequency of 21.9 , 29.6 , and 63.6% , respectively. Concentric remodeling (10.2%) and concentric left ventricular myocardial hypertrophy (9.3%) were rarely observed in the dogs .Mitral valve endocardiosis in dogs of small breeds is the most common nosological form of cardiovascular diseases ,15. ThisSymptoms of the left ventricular CHF in dogs with endocardiosis appear when blood stagnates in the pulmonary veins, and the disease starts with symptoms, such as shSortness of breath and decreased exercise tolerance . Furthermore, significant dilatation of the left atrium can lead to compression of the left bronchus, and hence cough is often observed in sick dogs ,35.The concept of structural and geometric remodeling of the heart include any changes in its shape, structure, or size that arise against the background of myocardial damage of any origin or overload of the heart muscle, both by volume and blood pressure. In human clinical cardiology, the following types of structural and functional cardiac remodeling are distinguished: Dilatation, concentric hypertrophy, eccentric hypertrophy, concentric remodeling, and normal geometry .Concentric remodeling is characterized by an increase in the wall thickness of the left ventricle and a decrease in its cavity without increasing the total mass of the myocardium. Concentric left ventricular hypertrophy is an increase in muscle mass and thickening of the left ventricular wall, which is formed when there is pressure overload on the heart muscle ,29. AccoThe eccentric type of remodeling is an increase in the left ventricular cavity and its mass due to volume myocardial overload. In endocardiosis of the mitral valve, the formation of this type of remodeling can be interpreted by retrograde systolic blood regurgitation into the cavity of the left atrium due to mitral insufficiency.It should be noted that we have not identified cases of a dilated type of left ventricular remodeling in dogs with mitral valve endocardiosis, which corresponds to the data obtained by other authors ,37.In the early stages of endocardiosis of the mitral valve of the heart in dogs, adaptive myocardial remodeling develops that ensure the effective functioning of the Frank–Starling mechanism (an increase in cardiac output during a tonogenic expansion of the left ventricle). In the late stages of endocardiosis, the death of cardiomyocytes occurs, which leads to the development of maladaptive remodeling and a progressive course of the disease.2; RMTd 0.47-0.83 relative units).In human medicine, echocardiographic parameters LVMMI and RMTd can be used for determining the type of left ventricular remodeling . In the All clinically healthy dogs revealed a normal type of the left ventricular chamber geometry. In the endocardiosis dogs, the normal type of left ventricular geometry was significantly less frequent. The presence of the normal geometry of the left ventricle in sick dogs can be explained by the long preclinical course of endocardiosis, which corresponds to Stage B of the ACVIM classification.Our study found that in dogs with mitral valve endocardiosis, the main type of remodeling was the eccentric hypertrophy of the left ventricular myocardium, which corresponds to the results of studies by other authors ,14,38,39In endocardiosis dogs, the ISRI index is highly informative. The progressive reduction of this parameter in sick dogs reflects the unfavorable association of the low contractile function of the left ventricle with a high degree of spherization.The identification of types of left ventricular remodeling has a significant practical value since, in most cases, it determines the course, prognosis, and choice of tactics for treating dogs with mitral valve endocardiosis. A promising direction for further scientific research is the identification of a correlation between the types of the left ventricular myocardial remodeling and the types of its diastolic dysfunction in dogs with endocardiosis, depending on the FC of CHF syndrome.Thus, this research showed the processes of the left ventricular remodeling formation that was found in patients with mitral valve endocardiosis. The degree of myocardial remodeling in sick dogs correlates with the FC of CHF syndrome. When comparing patients with endocardiosis and clinically healthy individuals, the myocardial mass, myocardial mass index, and sphericity index at the end of systole and diastole are significantly increased, and the ISRI and the end-systolic relative wall thickness of the heart are significantly reduced in the former group. In clinically healthy dogs, only the normal type of the left ventricular chamber geometry was reported. In patients with endocardiosis, there was no dilatation type of cardiac remodeling, and the normal type of the left ventricular geometry (56.4%) and eccentric hypertrophy (24.1%) was common, whereas concentric remodeling (10.2%) and concentric hypertrophy (9.3%) were rarely observed.YuAV, AAR, and BVU had the original idea for the study and carried out the design. AAR, EVK, IVB, and NIK collected the samples. EAN, IAB, VNG, and ANZ analyzed the data. YuAV, BVU, and EVK drafted the manuscript. The final draft manuscript was revised by all authors. All authors read and approved the final manuscript.


The slope of the relationship between segmental PreS and total systolic shortening (S) has been proposed as a non-invasive index of left ventricular contractility. The aim of this study was to correlate this novel parameter to invasive gold standard measurements of contractility and to investigate how it is influenced by afterload.max) and the pre-load recruitable stroke work (PRSW).In domestic pigs, afterload was increased by either balloon inflation in the aorta or by administration of phenylephrine while contractility was increased by dobutamine infusion. During all interventions, left ventricular pressure-volume measurements and trans-diaphragmatic two-dimensional echocardiographic images were acquired. The PreS-S slope was constructed from 18 segmental strain curves obtained by speckle tracking analysis and compared to the slope of the end systolic PV relationship  while ejection fraction increased (p<0.05). Emax, PRSW and the slope of the intra-ventricular PreS-S relation increased significantly during dobutamine infusion. Afterload increase led to increase in systolic blood pressure  and decrease of LV stroke volume and ejection fraction (p<0.01). The PreS-S slope was not influenced by loading conditions in concordance with the PRSW findings. The absolute values of the PreS-S slope did not correlate with Emax or PRSW. However, the change of the PreS-S slope in relation with different interventions demonstrated good correlation with changes in PRSW or Emax, .The slope of the PreS-S relationship is sensitive to changes in inotropy and is less load-dependent than conventional non-invasive parameters of left ventricular function. The magnitude of the change of this slope correlates well with changes in invasive contractility measurements making it an attractive parameter to assess contractile reserve or contractile changes during longitudinal follow-up of patients. Additionally, the slope of the dP/dtmax-end diastolic volume (EDV) relationship is also commonly used as an estimate of LV contractility. All these measurements are based on the Frank-Starling law of the heart that describes a direct relation between preload and the active force developed by the ventricle [max-EDV relationship was reported to be load dependent and sensitive to measurement variability while data on Emax is contradictory, with some studies reporting a degree of load dependency and non-linearity of the measurement under non-physiologic conditions while others do not [Despite the remarkable progress in cardiovascular research, the accurate (non-invasive) quantification of left ventricular (LV) contractile function remains a major challenge in clinical practice. As such, many studies have focused on identifying the best possible index of LV contractility taking into account its load dependency, its sensitivity to inotropic and chronotropic state and its reproducibility –11.Curreentricle ,8. Availentricle ,5,6,7,9.s do not –15. Of cs do not ,16. Thiss do not . This meHence, there is a clear need for a non-invasive methodology for the assessment of LV contractility that can not only be easily implemented in clinical routine, but that also shows to be reproducible, load independent and sensitive to contractile changes.In a previous study, we hypothesized that the slope of the intra-ventricular relationship between the regional myocardial stretch during atrial contraction, i.e. prestretch (PreS), and the associated regional systolic strain (S) could be an index of LV contractility . The sloThe purpose of this study was therefore two-fold: i) to contrast its sensitivity to changes in inotropy against gold standard methods of LV contractility and ii) to investigate the load dependency of the slope of the intra-ventricular PreS-S relationship.The experimental protocol was conducted in twenty-three domestic pigs of either gender (33.0 ±4.0 kg) in conformity to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was approved by the ethical committee of the Medical Faculty of the KU Leuven, Belgium.The animals were pre-medicated with an intramuscular mixture of zoletil (8mg/kg) and xylazine . Once positioned in dorsal recumbency and after endotracheal intubation, anesthesia was induced with an intravenous bolus of propofol (3mg/kg). The animals were connected to a ventilator and the initial tidal volume (9 ml/kg) was adjusted in each experiment to provide adequate arterial oxygen saturation. Continuous anesthesia was maintained with an intravenous mixture of propofol (10 mg/kg/h) and remifentanil (18 μg/kg/h). For prevention of thromboembolism and clotting of the vascular catheters, a bolus of heparin (10.000 IU) was administrated during instrumentation. After each experiment, animals were euthanized with an overdose of over-saturated potassium chloride solution under deep anesthesia.An 8Fr sheath was inserted in the right carotid artery (RCA) and used for the introduction of the conductance tip catheter  in the LV apex. A femoral artery and a femoral vein were accessed by deep inguinal puncture and a 9Fr introductory system sheath was placed in each access for the subsequent balloon catheter introduction. Under fluoroscopic guidance, the balloons were positioned in the inferior vena cava and the descending aorta, respectively.Finally, a transversal superior laparotomy was performed parallel to the costal margins for acquisition of echocardiographic data.In order to test the dependency of the PreS-S relationship on physiologic changes, the following interventions were performed. The interventions did not follow a strict order to avoid preconditioning bias.Afterload increase with balloon inflation (IAB). The balloon placed in the descending aorta was gradually inflated until an increase of minimum 15% of the basal LV pressure was obtained. In three pigs, the afterload increase was repeated during pharmacologic attenuation of the autonomic reflexes, which was induced by infusion of atropine methyl nitrate (3 mg/kg), propranolol hydrochloride (2 mg/kg) and hexamethonium bromide (20 mg/kg). This was performed to add extra datasets in which the reflex changes in the contractile state during caval occlusion were prevented and the intrinsic heart rate (HR) of the animal was maintained.Afterload increase with infusion of phenylephrine (IAP). In order to obtain a wide range of loading conditions, in a subgroup of animals, afterload was increased by administration of an α1-adrenergic agonist . In this scenario, the changes in afterload were the result of a more general vasoconstriction.Changes in contractility (IC). Contractility was increased by a continuous infusion of dobutamine (6 μg/kg/min) for 10 minutes.For all interventions, a set of echocardiographic images as well as PV loop data were acquired before, during and after the intervention. Before any data recording, the animal was given sufficient time to reach a stable condition.Echocardiographic data sets were acquired using a trans-diaphragmatic approach using a GE E9 system  equipped with a 2.5 MHz M5S transducer. Prior to the acquisition, the ultrasound system settings were optimized in order to optimize image quality. The protocol included grey scale recordings of the 2, 3 and 4 chamber views at a minimum frame rate of 50fps and Pulsed wave (PW) Doppler recordings obtained by sampling the LV outflow tract. For each recording, at least 3 consecutive cardiac cycles were acquired and stored for off-line analysis.Prior to the insertion, the micromanometer was calibrated at 38°C and zeroed at mid-thorax level. The fall in LV pressures and volumes during preload reduction by means of transient caval occlusion as a result of inflation of the balloon in the IVC, was continuously recorded using a MPVS Ultra® Pressure-Volume Loop System . Immediately after the PV loop acquisition, the IVC balloon was deflated in order to limit the time duration of the reduced preload condition as much as possible.The digital cine loops were analyzed offline using EchoPac version BT13 . All measurements were performed by a single experienced reader (OM). Left ventricular end systolic volume (ESV) and end-diastolic volume (EDV) as well as LV ejection fraction (EF) were measured from the apical 2 and 4 chamber views using Simpson’s biplane method as recommended in the current guidelines . Stroke Myocardial deformation was analyzed using a predefined 18 segments model of the LV (i.e. 6 segments for each of the 3 echocardiographic views). In contrast to what is typically done in strain echocardiography, the P-wave  rather than the onset of the QRS complex of the ECG was chosen as the beginning of the deformation cycle. As such, the underlying assumption was made that the ventricle remains in a condition of minimal stress during diastasis (i.e. its un-deformed state). The analysis was done by manually tracking the LV endocardial border and the automatically generated region of interest was adjusted as required. Tracking was visually verified and segments were excluded for further the analysis in case of poor tracking quality due to the presence of motion artifacts or reverberations.From the obtained segmental myocardial deformation curves , PreS wamax was measured by linear regression of the LV end-systolic pressure and volume changes during preload reduction. Similarly, PRSW was calculated by linear regression of the stroke work  and the EDV during IVC balloon inflation [a) was estimated as (ESP-EDP)/SV [All PV analyses were carried out using Labchart Pro . In order to calibrate the volumes measured by the conductance catheter, ESV and EDV as measured by echocardiography (cf. above) for each animal and at each interventional state were used. Enflation ,7,15. Fi-EDP)/SV . If duriClinical and echocardiographic characteristics are provided as mean ± SD for continuous variables, or as absolute number or percentage for categorical variables. Variables were checked to be normally distributed and to have equal variances. To compare data between the predefined study groups a paired t-test was used. Statistical analyses were performed using the software SPSS version 17.0 . Significance was set at a two-tailed probability level of p<0.05.The experimental protocol was successfully completed in 13 of the 23 animals. The exclusion of some of the data of 10 animals was done prospectively and due to both technical issues which hampered the interpretation and animal instability during the experiment. In detail, six animals were excluded due to: a) poor quality PV loops (n = 2), b) impossibility to acquire optimal echocardiographic recordings (n = 1), c) technical problems storing the data (n = 1), d) low correlation between the PreS and S values (n = 2), which was considered to be related to suboptimal image acquisitions since the correlation between PreS and S values was shown to be excellent. Additionally, four animals were excluded because of hemodynamic instability during the experiments due to arrhythmias or sudden death (n = 2) and suspicion of pericarditis (n = 2).max and 0,96±0,03 for PRSW. Similarly, the average correlation coefficient obtained while fitting the intra-ventricular PreS-S relationship was 0.75±0.09. Representative intra-ventricular pressure-volume relations and the correlative PreS-S relationships are given in max, PRSW and the slope of the intra-ventricular PreS-S relation increased significantly during dobutamine infusion. These results are presented in In response to the dobutamine infusion, systemic blood pressure did not change significantly while HR showed a marked increase. Compared to baseline values, the LV volumes decreased (p<0.05) while ejection fraction increased significantly (p<0.05). Emax or PRSW during these interventions, correlation coefficients of 0.69 (p<0.05) and 0.66 (p<0.05) were found respectively (No correlation was found between the absolute slopes of the intra-ventricular PreS-S relation and PRSW or ESPRV (p = NS). However, when correlating the changes in the slope of the intra-ventricular PreS-S relation with different interventions against the changes in Eectively . Interesectively .General echocardiographic and hemodynamic measurements obtained under baseline conditions and during the changes in loading are listed in max and Ea increased during increased loading (p<0.05). On average, SW did not change significantly during afterload increase.The values for the calculated indexes of contractility are presented in The major findings of this study are that: i) the slope of the intra-ventricular PreS-S relation accurately estimates intra-animal changes in contractile state and ii) the slope of the intra-ventricular PreS-S relation is–in contrast to conventional non-invasive functional measures–not significantly influenced by loading conditions.max, PRSW and PreS-S) significantly increased in response to dobutamine –in a segmental variation in wall stress during atrial contraction. As segmental strain is proportional to segmental stress this implies that strain during atrial filling (i.e. pre-stretch) is different for all LV segments. When LA functional changes would result in changes in LV pressure during atrial contraction, Laplace would indeed indicate that segmental stresses change accordingly and thus the induced strains (i.e. pre-stretch). Importantly however, the relative amount of pre-stretching of one segment with respect to another does not change as a result of such pressure changes if we assume we operate in the linear part of the myocardial stress-strain relationship; an assumption that seems reasonable given the relatively small pre-stretch resulting from atrial contraction (i.e. <10%). Indeed, increasing LV pressure will increase segmental stress (and thus pre-stretch) but the relative stress of one segment to another remains the same . Given that our method makes use of the slope of the prestretch-strain relationship, this slope will not be dependent on LA function as it is intrinsically accounted for. In fact, we believe this is one of the strengths of the proposed methodology.The study protocol required the use of anesthesia which may, in theory, interfere with myocardial resistance and elastance. Nonetheless, our study was a validations study against gold standard measurements of contractility and the potential influence of anesthesia would have impacted both methodologies and thus not invalidate the study results.Although in some animals the potential inotropic change due to acute afterload increase (i.e. as a consequence of the Anrep effect ) was avoSeveral studies have questioned the performance of ESPVR given that the relationship is not always linear when experimenting in conscious mammals and have recommended other types of non-linear curve fitting in order to obtain a more accurate index of LV contractility ,10–12,14Preload is managed solely by reduction by vena caval balloon inflation. The preload increment procedures were not performed due to time constraints . On the other hand, in a previous clinical study of our group we could demonstrate that the index was not influenced by preload increase .We recognize that dilated hearts will show limited myocardial pre-stretch as a result of atrial contraction similar to ventricles working on a steeper part of the pressure-volume relationship (i.e. less compliant ventricles). Although very small pre-stretch values may be difficult to measure reliably with the current echocardiographic methodologies, intrinsically the concept would hold as–even under these low average pre-stretch conditions–regional heterogeneity will remain resulting in heterogeneity in subsequent shortening thus allowing building a prestretch-strain relationship. Of course, the more globular shape of these dilated hearts will reduce the heterogeneity in regional curvature and therefore make the proposed methodology more difficult to apply.The applicability of the proposed methodology in conditions of dilated or hypertrophied hearts or in the presence of regional myocardial ischemic abnormalities (ischemic heart disease) remains to be investigated in future clinical studies.In the presence of atrial fibrillation or atrial flutter the pre-stretch cannot be reliably measured therefore the existence of these rhythm disturbances limits the use of the index.Finally, the study was performed only in animals with normal resting diastolic function. Future investigations should be carried in order to study the value of the PreS-S slope in conditions of abnormal diastolic function.The accurate quantification of LV function remains crucial in daily clinical practice. Despite the fact that several studies have proposed and investigated various indexes of myocardial contractility, EF is still the most commonly used index in clinical routine to assess the inotropic state of the heart. The obvious reasons for this are the fact that it can be measured non-invasively by multiple modalities in a relatively easy manner. However, it is well known that EF is load dependent Click here for additional data file.


An integrated approach for assessing ventricular pump function, diastolic compliance (EDPVR), myocontractility and pulmonary vascular resistance would be of clinical interest. In addition to pump function, MRI guided catheterization was demonstrated to accurately measure myocontractility and vascular resistance. We now extended this method for acquisition of the EDPVR. Subsequently, this approach was applied in patients with Fontan hemodynamic in which abnormalities in pulmonary vascular, myocontractile and diastolic properties are debated.The EDPVR was determined by synchronizing invasive ventricular pressures with cine and real-time MRI derived ventricular volumes and pulmonary/aortic blood flow measurements.In 7 pigs the MRI and conductance-catheter method (gold standard) were compared for measuring the EDPVR at rest and during dobutamine.Parameters of global function, myocontractility (ESPVR), vascular resistance and EDPVR were measured with MRI at rest and under dobutamine in 14 patients with Fontan circulation.Bland-Altman test showed agreement between the conductance-catheter and MRI method. In the pigs, there was in both ventricles during dobutamine a right/bottom shift of the EDPVR, the stiffness co efficient decreased slightly (p < 0.051). In the patients during dobutamine we noted failure to increase stroke volumes despite increased contractility and evidenced diastolic dysfunction. Active relaxation was inconspicuous but the EDPVR shifted towards the left/top, the stiffness constant remained unchanged. Pulmonary resistance decreased slightly (p = 0.058) and thus showed adequate response to augmented cardiac outputs.This novel MRI method provides differential information about diastolic, systolic and vascular function. The method evidenced that in Fontan patients diastolic dysfunction is an important pathophysiologic cause of heart failure.


Catheter based RF ablation is becoming an increasingly accepted treatment for refractory ventricular arrhythmias and late enhancement MRI can assist by providing anatomic maps of regions of scar which may form the basis for the arrhythmia. Unfortunately, many patients with ventricular arrhythmias have defibrillators (ICDs) implanted early in the course of their disease, prior to MR imaging assessment of cardiac structure, function, and scar burden. As ICDs are generally considered a contraindication to MRI, and the presence of a defibrillator may cause significant artifacts in the chest even if a study is performed, the use and utility of cardiac MR has not been studied in these patients.To evaluate the feasibility and safety of performing cardiac MR in patients with ICDs and refractory ventricular arrhythmias and provide an initial assessment of its utility for scar mapping related to RF ablation procedures.Six patients with ICDs suffering from refractory ventricular tachyarrhythmias were imaged within several days of catheter ablation procedures. All patients gave informed consent for performing MRI in the presence of an ICD. The devices were interrogated prior to and after the study; tachycardia detection and therapies were turned off, and the pacemakers were set to VVI mode at a rate of 40 bpm for the duration of the MRI.All studies were performed at 1.5 T. When possible, low SAR non-balanced gradient-echo cine and IR-prepped late-enhancement sequences were used, however real-time SSFP sequences were used in the presence of frequent ventricular ectopic beats. Imaging parameters were adjusted to minimize artifacts from the device.All studies were completed safely, no patients reported any discomfort, and there were no episodes of tachycardia requiring treatment. Post-procedure device parameters, including thresholds, lead impedances, and battery voltage were unchanged in all patients, and all devices could be reprogrammed to previous settings. Real time SSFP cine sequences were needed in two patients with frequent ventricular ectopic beats. As expected, spin echo sequences were less affected by artifact from the ICD generator than gradient echo sequences, with SSFP cine sequences showing greater artifact than non-balanced gradient echo cine sequences. Late enhancement images were particularly affected, with significant difficulties encountered in nulling the myocardium in regions affected by artifact. Increasing bandwidth, with resultant decrease in TE, decreased the size of the device related artifact but also impacted SNR. The degree to which cardiac evaluation was limited by artifact was most influenced by the size of the patient and distance from the generator to the left ventricle.Two patients were diagnosed with right ventricular cardiomyopathy with good visualization of RV structure, function, and scar. One patient had hypertrophic cardiomyopathy, and three non-specific LV cardiomyopathies, with variable limitations in visualization of the LV antero-lateral wall and apex. All patients did have evidence of focal myocardial scar in regions not affected by artifact; imaging information was consistent with electrophysiologic observations and was considered clinically valuable in all cases. Figure The results of this initial study suggest that cardiac MR for scar mapping may be performed safely in patients with ICDs under certain circumstances, giving clinically relevant results in those with refractory ventricular arrhythmias having RF ablation procedures.


The role played by the right ventricular (RV) dysfunction has long been underestimated in clinical practice. Recent findings are progressively confirming that when the RV efficiency deteriorates both the right and the left circulation is (significantly) affected, but studies dedicated to a detailed description of RV hemodynamic role still lack. In response to such a gap in knowledge, this work proposes a numerical model that for the first time evaluates the effect of isolated RV dysfunction on the whole circulation. Lumped parameter modelling was applied to represent the physio-pathological hemodynamics. Different grades of impairment were simulated for three dysfunctions i.e., systolic, diastolic, and combined systolic and diastolic. Hemodynamic alterations , arising from the dysfunctions, are calculated and analysed. Results well accord with clinical observations, showing that RV dysfunction significantly affects both the pulmonary and systemic hemodynamics. Successful verification against in vivo data proved the clinical potentiality of the model i.e., the capability of identifying the degree of RV impairment for given hemodynamic conditions. This study aims at contributing to the improvement of RV dysfunction recognition and treatment, and to the development of tools for the clinical management of pathologies involving the right heart. In the literature, the role played by RV has been largely underestimated compared to the left ventricle (LV) and, in the past, it was wrongly believed that RV could not affect cardiac output (CO) and systemic pressures6. Nowadays the importance of RV has been recognized, and its role in the cardiac hemodynamics has been highlighted8. Actually, the circulatory system is a closed-loop where the function of both ventricles is crucial. Therefore, not infrequently, impairment of one of the two ventricles precipitates impairment of the other9. Although LV dysfunction is most common, a recent study reported that RV myocardial infarction is not an infrequent problem, with an estimated occurrence of about 20–50% among patients with inferior myocardial infarction10. Unfortunately, the limited information about RV dysfunction effects does not allow to easily distinguish RV from LV dysfunctions, whereas it is evident that early diagnosis of RV myocardial infarction reduces the risk of death, cardiogenic shock, ventricular tachycardia and fibrillation, and atrioventricular block10.Left ventricular systolic and diastolic dysfunctions have been studied extensively and are described as main causes of heart failure (HF)isolated RV dysfunction on global cardiovascular conditions. We are aimed at highlighting to what extent RV (dys)functional properties impact blood pressures and flows, so that the understanding of the “forgotten ventricle”7 physiopathology improves, and an easier clinical management of ventricular dysfunction will be gained in the future. The paper is structured as follows. In “In the present study, we implemented a lumped parameter model of the complete circulation in order to analyse for the first time the consequences of 14. Moreover, when the closed—rather than the open-loop configuration is adopted, 0D models fully couple the simulated state, either healthy or pathological, and the resulting hemodynamics, with no need to prescribe arbitrary flow or pressure behaviour15.In order to carry out an extensive analysis of different degrees of right ventricular dysfunction, we developed a closed-loop lumped parameter (0D) model able to reproduce the entire cardiovascular system. This choice represents the best cost/benefit option since 0D models provide reliable results in terms of pressure and flow waves with low computational costR) and the compliance due to vessel elasticity (C); whereas the vascular beds were represented considering only the dissipation effects (represented by R). The heart was represented by the elastance model16, employing a time-varying elastance (E(t)) to reproduce the myocardial activity17. E(t) was simulated via a ‘two-Hill’ function which accounts for contractile (g1) and relaxation (g2) phases of the cardiac cycle ask is a factor to guarantee that The circulation was simulated considering the scheme of Fig. The two functions p(t)) readsV(t) and From Eq. , the pre12. Detailed equations of all the elements that compose the lumped model are reported in the Last, the presence of the valves was considered with linear resistance effects when they are open. Notice that valves leaflets dynamics was assumed as instantaneous i.e., the “on/off diodes” model was adopted since normo-functioning valves were consideredode15s, solving a closed-loop system up to convergence i.e., when the relative difference between the initial values of the variables at two subsequent heartbeats was lower than 1e−4. Such a condition was usually attained within 30 cycles, requiring about 1 min of computational time with a high-performance desktop PC. Results were extracted after reaching the periodic steady state.The resulting system of ODE equations was run exploiting the built-in MATLAB function First, the model was set up to reproduce the physiological hemodynamics of a representative healthy person.2, having an heart rate (HR) of 75 bpm, a cardiac output (CO) of 6.5 L/min, and a perfusion pressure of 97 mmHg17. Moreover, a sensitivity analysis to verify the influence of parameters on the model was carried out  was computed as 19), and the venous compliance as 20. For the pulmonary circulation, the value of the pulmonary vascular resistance (PVR) was taken from the literature21  of Eq.  was requStarting from the healthy configuration, we defined the alterations required to simulate the RV dysfunction.The dysfunction of the ventricle is due to pathologies that can affect both/either the contractility of the myocardial fibers and then their capability to eject blood i.e., systolic dysfunction, and/or the ventricular passive mechanism of filling i.e., diastolic dysfunction. Accordingly, we analysed the global hemodynamics considering the following scenarios: (i) isolated right ventricular systolic dysfunction, (ii) isolated right ventricular diastolic dysfunction, and (iii) combined systolic and diastolic dysfunction.RV dysfunction is caused by the same types of impairments that affect LV i.e., systolic dysfunction is mainly determined by a reduction in RV contractile force whereas diastolic dysfunction is mostly due to increased ventricular stiffness. Thus, the parameters of the dysfunctional right heart were determined in analogy with those usually adopted for the LV impairment;secondary mechanisms due to the primary RV dysfunction e.g., adaptation mechanisms such as the variations of the systemic vascular resistance, were excluded to avoid additional mechanisms in the evaluation of the pathological hemodynamics given by a primary RV dysfunction.Specific descriptions of the mechanisms of ventricular impairment are briefly described in the following subparagraphs.As mentioned in the Introduction, few data are available to date for modelling the impairment of the right ventricle. In this work, the following assumptions were hence made:24. SD is here reproduced through a reduction of the maximal contraction force, 26.Systolic dysfunction (SD) refers to the ventricle’s inability to pump the adequate amount of blood due to impaired myocardial function, increased afterload, structural abnormalities, or the combination of the previous diseases of Eqs. ). Indeed27. In the present work, we focused on the most life-threatening condition (grade III of diastolic dysfunction) i.e., the restrictive filling. In this stage of DD, the ventricular wall stiffness (28.Diastolic dysfunction (DD) refers to the ventricular inability to fill its cavity due to decreased distensibility, delayed relaxation, and abnormal filling. For DD, there are three patterns of impaired filling, which represent progressively worse diastolic dysfunctionp was adopted for both SD and DD for sake of simplicity in order to analyse the relative weight of each of them on the resulting hemodynamics.Combined diastolic and systolic dysfunction (CD) results from the combination of SD and DD, and it was reproduced by superimposing the two previous dysfunctions. The same grade of impairment p) in the range 0% –100%  to simulate the RV dysfunction. Particularly, we defined the value of the parameters in the presence of a complete (systolic/diastolic) dysfunctional ventricle (p = 100%) and we varied linearly all the parameters involved. To simulate the systolic dysfunction, p = 0%) to 0.430 s and 0.723 s (p = 100%), respectively. In the DD case, we increased 29. Analogously, to simulate CD, Once the parameters reproducing the hemodynamics of a representative healthy person were determined, we introduced the percentage of impairment  and DD i.e., they suffer from a condition that matches our definition of combined RV dysfunction since PAH is known to be associated with severe systolic dysfunction31. To setup the model, we identified the degree of impairment as follows. First, knowing that the systolic functionality alters ventricular performances i.e., EF32, we determined the systolic dysfunction required to obtain the EFRV reduction reported by the authors30. Second, we tuned the degree of diastolic dysfunction to minimize the difference between the predicted results and measured data30.To compare model predictions and a real scenario, the in vivo investigation of Browning et al.This article does not contain any studies with human participants or animals performed by any of the authors.Table p increases, the right atrial (RA) pressure increases. The exacerbation of the impairment also flattens the late-systolic peak (v-wave) and emphasizes the end-diastolic peak (a-wave), despite the unaltered right atrial functionality. On the other hand, RV pressure exhibits a marked reduction of the systolic peak and an increase of the diastolic pressures. On the contrary, the pulmonary arterial pressure (PPuA) substantially reduces on the whole heartbeat. Both the two pressures curves have flattened profiles as the pathology worsens and the systolic phase increases according to E(t) displayed in Supplementary Fig. ra is offset by the increase in the diastolic Prv, resulting in a reduction of the E wave. Such a reduction is partly compensated by an increase of the A wave on the tricuspid valve flow (Qtv) , whose maximum is observed for p = 80%. The loss of contractility affects also the flow across the pulmonary valve (Qpv)  Fig. a4. From thy case 00 mL/s, E(t) function, the shape of all the variables during the cardiac cycle remains unaltered for the different grades of p. The simulated pressures in the right atrium and in the pulmonary artery exhibit a positive and negative shift with p increasing, respectively. Consistently, Prv decreases during systole and increases during diastole as DD increases. The flow between RA and RV (Qtv), due to their pressure variations, shows higher peaks for both the E and A waves., The former results to be characterized by an increasing flow deceleration and the latter by an increasing flow acceleration , the pulmonary valve opening is anticipated at the end of diastole i.e., atrial contraction is causing pressure to rise above pulmonary arterial pressure, such that the pulmonary valve opens before the onset of ventricular systole , DD oversteps for moderate dysfunction (p > 40%), and CD goes beyond the ranges for p > 30%. All the dysfunctions depress the ventricular functionality resulting in hypoperfusion . The response in terms of EF highlights the role of RV contractility , and in the CD case, the loss of contractility determines an EF decrement up to p = 70%. For more severe CD impairment EF is almost constant. As already pointed out for the PV loops, RV dysfunction causes a diminution of LV performance for all types of dysfunction  survive into adulthood with quite a good life quality one might presume that RV is nonessential indeed. However, in vivo evidences are pointing out that the RV plays a key role in the onset and progression of a number of diseased conditions as well as in exercise capacity35. So, in order to contribute to improve the knowledge of right ventricular (dys)function effects on the complete circulation hemodynamics, we studied the isolated RV dysfunction by physically based numerical simulations.The importance of the right ventricle has often been underestimated in the clinical practice and research40. In particular, hemodynamics of the right side is found to be well represented in all its characteristics, right heart flow waveforms included41.We built up a lumped parameter model of both the right and left circulation that proved its capability to reproduce the physiological condition with pressures, flows, and global hemodynamic variables in a very satisfying agreement with literature data of healthy subjects26, emerged as crucial in order to obtain results in accordance with clinical evidences. In particular, the increase in ventricular end-diastolic pressure and the reduction in the systolic one, well known for the left ventricular failure42, has been recently reported also in the case of RV systolic impairment43. This result is clearly represented by the model in presence of right systolic dysfunction, when RA is forced to increase its pressure to overcome the pressure into the overfilled ventricle and open the tricuspid valve, while Ppua decreases44. At the same time, the computed Qtv E wave disappears due to the reduction of the tricuspid pressure gradient, in part compensated by the increase of the A wave. Notice that a similar atrioventricular valve flow is known in left ventricular disfunction45. Hence, we can speculate that it is the impairment of the right/left systolic function the pathologic condition that leads to such a right/left atrioventricular flow behaviour. We also observed that, importantly, when the contractile activity is absent (p = 100%), the model captures the nearly constant Prv and Qpv. Such a result, somehow expected, shows that in absence of any contractile activity the right ventricle behaves like a passive conduit i.e., a condition similar to the spontaneous evolution of the Fontan circulation appears46, but with the RA still contracting.A large number of information worth of discussion emerges from model simulations when RV dysfunction is taken into account. We first recall that our model includes for the first time prolonged cardiac time intervals among the mechanisms that drive the isolated systolic dysfunction (SD) condition. Indeed, the variation of systolic time with the rate of impairment, which is peculiar to the ventricular systolic dysfunctionrestrictive filling the ejection fraction EFRV is almost preserved. In other words, the ventricle exhibits the well-known features of heart failure with preserved ejection fraction (HFpEF) i.e., of the pathology that is usually attributed to LV34. Such an evidence seems quite interesting since it might help in answering some of the questions left open in Gorter et al.34 about “the determinants of RV dysfunction in HFpEF”.While it is true that EFRV is substantially maintained, on the other hand DD results to alter pressures and flows. In this sense, it is worth noting that model predictions for severe impairment show the appearance of a secondary peak in Qpv at late diastole which, according to Gatzoulis et al.47 for Tetralogy of Fallot patients, could be ascribed to atrial contraction. Notice that the debate about the aetiology of such a secondary peak in Qpv is still open48. Among possible explanations48, we here recall the one that ascribes the peak appearance to the atrial, ventricular, and pulmonic pressure state in restrictive filling, which forces the ventricle to behave like a ‘passive conduit’47. Indeed, since the model assumes isolated dysfunction and does not account for adaptive processes, the ventricular stiffness does seem to be the actual leading cause of the diastolic flow peak occurrence.For what the isolated diastolic dysfunction (DD) is concerned, model results suggest that when the right ventricle suffers from Finally, in the combined systolic and diastolic dysfunction (CD) the effects of the two previous dysfunctions sum, and both their footprint can be easily recognised in CD simulations’ results. However, the superposition of SD and DD follows a non-linear behaviour, so that CD hemodynamics exhibits an overall worst performance.49, and the computed EDPVR increase well compares to that typically occurring in diastolic dysfunction50. In the CD case, the right ventricle attempts to dilate for the lower contractility due to SD, but the increased passive stiffness due to DD opposes this volume dilation. For p 51. Notice also that the effect of RV systolic dysfunction on LV is more severe in the CD than in the SD case. This result is not surprising since the loss of the passive action of the right myocardium, expressed by its relaxation, worsens the ventricular working.The hemodynamic alterations visible in calculated PV loops Fig.  can also53 are found to be overpassed for all the three different types of reproduced dysfunction, although for different degrees. Such an occurrence strengthens the idea that the correct functioning of the right ventricle during the whole cardiac cycle is of crucial importance in assuring overall physiological hemodynamic conditions. Passing now to EF, we observe that, as expected from PV loops’ evidences, our results confirm the strong interaction between the two ventricles. In particular, the computed EF behaviour suggests that both EFRV and EFLV have to be evaluated in right diseases . Indeed, van der Ven et al.51 recently pointed out that the role of LV in Tetralogy of Fallot can not be neglected, despite LV parameters are not considered in current guidelines for the assessment of the most appropriate timing of intervention51.For what CVP and CI are concerned Fig. a,b, clin30 , the RV dysfunction model, implemented with the LV impairment, may be appropriate to recognize the hemodynamics due to the left HF or associated to primitive right HF (bi-ventricular failure). This distinction is particularly important when a left ventricular assist device (VAD) is required. In the case of induced right HF, the right ventricular function recovers, partially or completely, after the left VAD implantation. Conversely, when the right ventricular dysfunction occurs, usually a bi-VAD is the best clinical option.The diagnosis and treatment of diseased conditions might hence benefit from the application of the model thanks to its ability in determining flow and pressure changes as a result of RV dysfunction. For example:Limitations: (i) Cardiac valve flow was modelled according to a simple linear flow/pressure gradient relationship, which is likely the reason why Qao and Qmv (E/A ratio) are found to have peaks somehow higher than physiological ones40. Moreover, the adoption of ‘on/off diodes’ as heart valves model results in the absence of reverse flow at the final stage of the open valve phase. (ii) Neither physiological compensatory mechanisms e.g., ventricular remodelling and venous constriction, nor secondary diseases e.g., tricuspid valve insufficiency54, were accounted for in the model since we aimed at highlighting primary RV dysfunction effects alone. Future improvements: (iii) The adaptation of more complex flow/pressure gradient relationships for cardiac valve flow is expected to overcome the issues highlighted at previous point (i) . In particular, the inclusion of valve dynamics will allow realistic simulation of conditions affected by both RV dysfunction and diseased valve(s) (stenotic and/or incompetent). (iv) Further insights are also expected from taking into account fluid–structure interactions e.g., the remodelling of cardiac chambers as a compensation of impaired ventricular function. (v) Last but not least, further development can arise from taking into account sex differences in model parameter values and/or cardiovascular functional response i.e., differences that has been recognised as pivotal in both healthy and pathological hemodynamics58.Finally, study limitations and possible future improvements can be summarized and commented. Our study highlights the effect of RV (dys)function on the overall hemodynamics. The 0D circulation model seems to correctly simulate the pressures and flows in both the pulmonary and systemic circulations. Changes in RV functions lead to significant modifications of the overall hemodynamics, affecting also LV output due to a decreased preload. To the best of our knowledge, there is not such a previous engineering work aimed at understanding the hemodynamic implications of the development of RV impairment. In addition, the model matches clinical data of patients presenting RV diseases, providing a first step towards the set up and the assessment of a numerical tool able to support clinicians to improve the knowledge and the understating of the role played by RV on the blood circulation with potential future benefits in the diagnosis and treatment of RV pathologies.Supplementary Information.


ObjectiveTo evaluate the mid-term effects of ivabradine on right ventricular functions in patients with heart failure.MethodsA prospective study was conducted on 52 patients who had heart failure in normal sinus rhythm . Right ventricular functions were measured at baseline, after one month and one year by conventional and tissue Doppler echocardiography imaging. The parameters, right ventricular (RV) longitudinal strain (LS), RV systolic longitudinal strain rate (LSRs), RV early diastolic longitudinal strain rate, and late diastolic longitudinal strain rate, were evaluated by apical four-chamber grayscale imaging through the free wall of RV in accordance with the automated function imaging protocol.ResultsDuring the follow-up, the pulmonary artery systolic pressure (PASP), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI), E peak, and A peak values were similar to the basal values. While comparing the basal values of the global longitudinal systolic strain (GLS), LS, LSRs, longitudinal strain rate diastolic early filling (LSRe), and longitudinal strain rate diastolic late filling (LSRa), there were no differences in the first month but a significant increase was observed on one-year follow-up (p<0.001).ConclusionAt the one-year follow-up, the heart failure patients who were given ivabradine treatment showed an improvement in the right ventricular function assessed by the new echocardiographic techniques. Heart failure is a prevalent health problem and is closely associated with high morbidity and mortality. Despite the advancements in treatment strategies, morbidity and mortality rates remain high -2. The pIvabradine is a novel selective inhibitor of cardiac If (pacemaker) current, which not only reduces the heart rate but also has anti-ischemic and anti-anginal effects . It has Conventional myocardial assessment by tissue Doppler imaging (TDI) echocardiography has some disadvantages like angle dependence, limited spatial resolution, and one-dimensional deformation analysis. Recently, these limitations have been resolved through advances in two-dimensional speckle tracking echocardiography (STE), and STE has become the preferred technique for this purpose .Studies demonstrating the positive effect of ivabradine on left ventricular remodeling in heart failure patients were conducted . HoweverThis work was previously presented as an abstract at the 2nd Cardiovascular Academy Society Congress on October 06, 2016.PatientsThis study was conducted prospectively between January 2016 and June 2016 in a single tertiary healthcare center. We studied consecutive 52 adult patients with stable symptomatic chronic heart failure (New York Heart Association (NYHA) class II-III) with left ventricular ejection fraction (LVEF) ≤35 %, and who were in sinus rhythm with a resting heart rate of ≥70 beats/ per minute (bpm). All patients were also receiving guideline-recommended therapies such as beta-blockers (proven or maximum tolerable dose), angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blocker (ARB)), and/or anti-aldosterone agents. The exclusion criteria were as follows: recent (<2 months) myocardial infarction, ventricular or atrioventricular pacemakers, atrial fibrillation or flutter, chronic kidney disease (glomerular filtration rate (GFR) <30), morbid obesity, significant valve disease, ascending aortic aneurism, chronic obstructive pulmonary disease, chronic pulmonary thromboembolism, and poor echocardiographic image quality. The study complies with the Declaration of Helsinki. The research protocol was approved by the institutional review board and informed and signed consent was obtained from all patients.In accordance with the current treatment algorithm, the starting dose was 5 mg ivabradine twice daily. Afterward, it was up-titrated over 14 days to a target dose of 7.5 mg twice daily unless the heart rate was <60 bpm or symptomatic bradycardia. The dose was adjusted to 7.5, 5, or 2.5 mg twice daily according to the resting heart rate and tolerability. The clinical, electrocardiographic, and echocardiographic measurements of the patients were recorded at baseline and the first and 12th months after the initiation of ivabradine.Transthoracic echocardiographyEchocardiographic examinations were performed by EPIQ 7 digital ultrasound scanner  in the left lateral decubitus position from multiple windows. All measurements were taken by two experienced cardiologists who were blinded to the clinical status of the patients. The two-dimensional (2D) and pulse wave Doppler echocardiographic studies were performed according to American Echocardiography Association's criteria . A singlRight ventricular strain and strain rate measurementsFor speckle tracking analysis of RV, apical four-chamber view images were obtained using two-dimensional gray-scale echocardiography. The mean frame rate was set as 60 per second (between 50 and 80 per second). Recordings were performed for the images that were having the best endocardial border delineation. Three consecutive cardiac cycles were recorded for all measurements. Afterward, records were processed by tissue Doppler imaging (TDI) data and analyzed offline using dedicated software  Figure . The firStatistical analysisThe results were analyzed with the Statistical Package for the Social Sciences (SPSS) for Windows 15.0 . Differences in proportions between groups were compared by using the chi-square or Fisher’s exact test, where appropriate. For the normality of the distribution for parameters and for differences for paired variables, the Shapiro-Wilk and Kolmogorov-Smirnov tests were used. The differences among the three measurements such as baseline to one year were evaluated by Friedman's two-way analysis of variance by ranks. When the p-value from the Friedman test statistics is statistically significant, the multiple comparison test was used to know which time points differ from which others. The reliability of the study was assessed for randomly selected 10 patients by using the intraclass correlation coefficient (ICC). Descriptive statistics are summarized as counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Any p-value less than 0.05 was considered statistically significant.The baseline demographic and clinical characteristics of the study patients are summarized in Table The medication details of the patients are demonstrated in Table A comparison of basal and follow-up (one month and one year) values measured by transthoracic echocardiography is presented in Table In the TDI parameters measured at the lateral tricuspid annulus, there was a significant increase in systolic Sm and diastolic Em and a decrease in diastolic Am at the one-year follow-up. There was no change in the peak myocardial velocity during isovolumic contraction (IVV) and myocardial acceleration during isovolumic contraction (IVA) parameters during the follow-up Table .Two patients were excluded from the study because of poor image quality. To obtain the average strain and strain rate, the number of non-readable RV segments was within the acceptable limits. A comparison was made for the basal and follow-up values in terms of LSS, LSRs, LSRe, and LSRa values, measured from the basal, mid, and apical aspects of the free wall of the RV. In comparison to the basal parameters, there was no change at the one-month follow-up; however, there was an increase at the one-year follow-up (p<0.001) Table . The twoIn this study, ivabradine showed functional improvement in the right ventricle but not a morphological one after one year of treatment as demonstrated by the new echocardiographic techniques. There are several methods for routine practice to evaluate the right ventricular function. Two-dimensional strain, which is done by using standard two-dimensional views, can perform strain measurements with speckle tracking. Moreover, in comparison to conventional strain measurements, it has low angle dependency and high reproducibility. STE can measure intramyocardial velocities in three dimensions  and shows very low inter- and intraobserver variability. Recent studies have demonstrated that this method is practical and efficient for the evaluation of the right ventricular function in routine practice -20. SimsIn recent years, the importance of the hemodynamic stability of the right ventricle (RV) for the preservation of the other organ functions has been realized. The isolated right ventricular failure has higher mortality than the isolated left heart failure . The mosIvabradine is a new pharmacological agent, which is a specific inhibitor of the If channel on the sinoatrial node . The onlLimitationsThis study should be evaluated in light of some limitations. First, our study was a non-randomized, two-centered study composed of a limited number of patients. Additional clinical randomized trials with greater participation can offer more reliable statistical data. Second, the measurements used to predict RV dysfunction were not independent parameters. Furthermore, RV functions were measured by only longitudinal strain and strain rate parameters but not at the radial and circumferential levels. Although radial and circumferential measurements have been extensively studied in LV strain analysis, their importance in the right ventricle is not well-known. Also, their estimation is more technically challenging than the LV due to the relatively thinner wall and complex geometry of the RV. Finally, the AFI protocol is software primarily produced for LV strain analysis. However, we used the AFI protocol for RV strain analysis depending on an experimental study wherein its utility was shown in RV strain analysis . NeverthIn the current study, a one-year follow-up of patients with heart failure receiving ivabradine treatment was investigated by conventional echocardiography and STE. The right ventricle showed functional improvement but did not change morphologically. We believe that these findings should be tested with prospective and larger studies.


To assess the ability of cine-MRI to identify potential responders to cardiac resynchronization therapy (CRT).40 patients with reduced ejection fraction (28 ± 11%), with (n = 21) or without (n = 18) left bundle branch block underwent cine-MRI and tissue-doppler imaging echocardiography (TDI). Time to peak systolic velocity (TPV) was measured by TDI for the septal, anterior, lateral and inferior left ventricle (LV). Time to peak contraction (TPC) was assessed visually for corresponding regions by cine-MRI. Left ventricular (LV) dyssynchrony was defined as the maximum delay of TPV- and TPC between opposing regions for TDI and cine-MRI, respectively. Correlation and agreement between TDI and cine-MRI were calculated. The ability of cine-MRI to identify patients with relevant echocardiographic LV dyssynchrony (defined as >65 ms) was assessed by ROC analysis.A strong correlation between LV dyssynchrony by TDI and cine-MRI was found . Bland-Altman analysis showed a large difference of absolute values between both methods (mean difference 108 ± 104 ms). ROC analysis revealed an optimal cut-off value for cine-MRI of > 145 ms to identify patients with relevant echocardiographic LV dyssynchrony . The ability of cine-MRI to discriminate between patients with and without relevant echocardiographic LV dyssynchrony was excellent .Visual assessment of LV dyssynchrony by cine-MRI can identify potential responders to CRT.


Left ventricular hypertrophy (LVH) is a common presentation encountered in clinical practice with a diverse range of potential aetiologies. Differentiation of pathological from physiological hypertrophy can be challenging but is crucial for further management and prognostication. Cardiovascular magnetic resonance (CMR) with advanced myocardial tissue characterisation is a powerful tool that may help to differentiate these aetiologies in the assessment of LVH.The use of CMR for detailed morphological assessment of LVH is well described. More recently, advanced CMR techniques  have been used. These techniques are highly promising in helping to differentiate key aetiologies of LVH and provide valuable prognostic information.Recent advancements in CMR tissue characterisation, such as parametric mapping, in combination with detailed morphological assessment and late gadolinium enhancement, provide a powerful resource that may help assess and differentiate important causes of LVH. Left ventricular hypertrophy (LVH), defined as an increase in LV mass or wall thickness, is commonly encountered in clinical practice and is associated with structural myocardial changes . It indeThere are multiple causes of LVH, ranging from physiological adaptation to athletic training or increased afterload (such as hypertension or aortic stenosis), to more severe pathological hypertrophy, as seen in hypertrophic cardiomyopathies and infiltrative/storage diseases. Although clinical and family history, along with physical examination, may narrow the differential diagnosis, the exact aetiology can remain unclear. Given that the management and prognosis of different aetiologies of LVH may differ significantly, an accurate diagnosis is crucial.Cardiovascular magnetic resonance (CMR) is the current imaging gold standard for accurate and reproducible assessment of cardiac mass, volumes and function –7, and iLate gadolinium enhancement (LGE) is the standard CMR myocardial tissue characterisation technique. It allows differentiation of ischaemic and non-ischaemic heart disease via characteristic enhancement patterns, and is excellent for detecting areas of focal scarring/fibrosis . LGE is Novel parametric mapping techniques, such as T1 and T2 mapping, allow advanced tissue characterisation via directly quantitative pixel-wise maps . DetaileSimilar to native T1 mapping, T2 mapping also reflects global signal from the intra- and extra-cellular myocardial compartments. An elevated T2 generally indicates increased free-water content and is typically used to detect acute myocardial inflammation and oedema ••. AlthoAdditionally, there is increasing interest to quantify the myocardial extracellular volume (ECV), which may act as a surrogate marker for diffuse interstitial fibrosis after exclusion of confounding factors –27. ECV Other advanced CMR techniques to assess LVH include methods to evaluate myocardial contractility and pathological myofibre disarray. Myocardial deformation (strain) parameters, such as global longitudinal strain (GLS) and global circumferential strain (GCS), have emerged as sensitive markers of early subclinical myocardial dysfunction. They are strong, independent predictors of mortality in patients with heart disease, even after accounting for left ventricular ejection fraction (LVEF) and LGE burden . FeatureDiffusion tensor imaging (DTI) is an emerging CMR technique that may provide important insights into hypertrophic disease processes by characterising myocardial microstructural changes . It can These powerful CMR techniques play an important role in differentiating pathological and physiological hypertrophy. The next section will focus on their application in the most commonly encountered LVH phenotypes, namely hypertrophic cardiomyopathy (HCM), infiltrative/storage diseases , increased afterload  and physiological remodelling in the athletic heart. Key differentiating CMR characteristics are displayed in Fig. Hypertrophic cardiomyopathy (HCM) is the most common genetic heart muscle disease  and the leading cause of sudden cardiac death (SCD) in the young . It is dCMR has a Class I recommendation in current HCM guidelines by both the European Society of Cardiology (ESC) and American College of Cardiology (ACC) if echocardiography is insufficient, if there is ongoing diagnostic uncertainty regarding hypertrophic phenotypes or if additional information is required , 38. AltThe presence and pattern of LGE is particularly useful for diagnosis and risk stratification in HCM. LGE has been shown to correlate with, although not specific for, areas of increased myocardial collagen and fibrosis on histological analysis of myectomy specimens and explanted hearts –41. A coAdvances in T1 mapping and ECV quantification have allowed non-invasive CMR assessment of diffuse myocardial fibrosis or other changes that may be missed by LGE. In patients with dilated cardiomyopathy (DCM) or HCM, even segments with normal wall thickness and no LGE may have increased T1 values, suggesting underlying disease processes beyond those assessed by LGE . FurtherMyocardial strain imaging may also help differentiate between pathological and physiologic hypertrophy. One recent study reported that impaired CMR-FT GLS may differentiate between HCM and hypertensive heart disease, with a similar  discriminatory capacity to tissue characterisation  biomarkers . HoweverFinally, diffusion tensor imaging (DTI) is an important recent CMR advancement for diagnosis and risk stratification in HCM with good reproducibility , 55, 56.Cardiac amyloidosis is a rare systemic disease characterised by progressive myocardial infiltration of misfolded protein fibrils. The resulting phenotype is an infiltrative cardiomyopathy with increased myocardial wall thickness, conduction disease and subsequent heart failure. Although often mislabelled as hypertrophy, the increased wall thickness is due to extracellular expansion from infiltration rather than true cardiomyocyte hypertrophy. Two main forms of amyloid affect the heart: light chain (AL) amyloidosis, where amyloid fibrils are derived from monoclonal immunoglobulin light chains in association with a plasma cell dyscrasia , and traAL amyloidosis generally takes a more fulminant course and has a poor prognosis; untreated, the median survival from onset of heart failure may be approximately 6 months . More seATTR amyloidosis has a more indolent and slowly progressive clinical course, with median survival approximately 60 months from first heart failure presentation ••. DespiMorphologically, cardiac amyloidosis is characterised by increased biventricular wall thickening , thickening of the subvalvular apparatus and atrial septum, biatrial dilatation and pericardial effusion. LVEF is generally preserved until the end stages of disease. Echocardiography is the most used diagnostic imaging test, with the characteristic apical sparing pattern on strain imaging often helping to differentiate amyloid from other causes of LVH . HoweverIncreasingly sensitive advanced cardiac imaging techniques, such as technetium-labelled bone scintigraphy (e.g. 99mTc-DPD scans) and CMR, have led to greater recognition and earlier detection of cardiac amyloid. DPD scans , 64 in pCMR tissue characterisation provides a radiation-free alternative to differentiate cardiac amyloid from other causes of LVH. Characteristic LGE patterns are seen; myocardial and blood-pool gadolinium kinetics are abnormal , and theParametric T1 mapping plays a prominent role and offers potentially improved sensitivity for the early detection of amyloid compared with LGE . Native Like echocardiography, CMR-FT studies have shown the presence of marked relative apical sparing of longitudinal strain patterns in patients with cardiac amyloid. One study showed that regional reductions in longitudinal strain helped to differentiate cardiac amyloidosis from other hypertrophic mimics, such as HCM and AFD, with a base-to-apex quantitative gradient of LGE burden also identified . MyofibrAnderson-Fabry disease (AFD) is an X-linked inherited metabolic disease caused by the reduction or absence of a functional α-galactosidase A enzyme. This results in lysosomal accumulation of glycosphingolipids in many organs and tissues . The cliMorphological imaging assessment may display characteristic hypertrophic features but is not sufficient alone to diagnose AFD. For example, although the pattern of LVH is usually concentric, RV hypertrophy, asymmetric septal hypertrophy and even LVOT obstruction may occur, indistinguishable from that seen in sarcomeric HCM . Tissue T1 mapping plays a prominent role in the diagnosis of AFD ••. SigniMyocardial strain imaging has also been investigated in AFD. Impaired longitudinal strain correlates with reduced native T1 values and increased LV wall thickness and mass . Loss ofOther lysosomal and glycogen storage disorders  are also classically associated with LVH. These conditions are often progressive and may manifest extreme hypertrophic phenotypes. Given their rarity, there is little data available on using advanced cardiac imaging to differentiate them from other causes of LVH , 93. ForHypertensive heart disease (HHD) and aortic stenosis are common conditions which cause adaptive LVH due to increased afterload. Systemic hypertension is one of the most common chronic diseases, and is a well-established cardiovascular risk factor . In hypeLVH secondary to HHD is more likely to regress with anti-hypertensive treatment on serial imaging (in contrast to hypertrophic or infiltrative cardiomyopathies), but this is not particularly sensitive . MaximalThe diagnosis of significant aortic stenosis (AS) is generally apparent from clinical history, examination and echocardiography. However, there may be considerable variation in the LV hypertrophic response, with the pattern and severity of LV remodelling not always correlating with the degree of valve narrowing . AsymmetMyocardial fibrosis occurs as part of the hypertrophic response to increased afterload, and is a key pathological component of the transition to heart failure and adverse events in AS. Non-ischaemic mid-wall fibrosis seen on LGE is well described as an early marker of LV decompensation and predictor of adverse cardiovascular outcomes, and does not appear to regress with valve replacement –104.Native T1 values increase with worsening severity of aortic stenosis and symptom status, and correlate significantly with histological fibrosis and collagen volume fraction on myocardial biopsy . It is iInterrogation of these T1 signal changes using a vasodilator stress agent in severe AS patients shows a ceiling of stress T1 reactivity similar to healthy volunteers, with a blunted overall delta T1 response  . NormaliThis principle should be remembered when looking at post-contrast T1 mapping and ECV. An elevated ECV correlates with markers of LV decompensation in severe AS , 108, whPhysiological adaptation to regular intense physical training may result in enlarged cardiac chamber size and increased LV wall thickness and mass . There iApproximately 2% of white athletes and up to 13% of black athletes have an LV wall thickness of 13–16 mm  , which mCMR tissue characterisation and assessment of myocardial fibrosis are helpful discriminators between physiologic and pathological LVH, with typical LGE patterns more suggestive of HCM. However, absence of LGE cannot exclude HCM, given its presence in only 50–65% of cases. Parametric mapping may also be useful: one study showed normal T1, T2 and ECV values in athletes with increased LV mass, reduced LVEF and increased LV volumes . Another2 max) than patients with HCM [Exercise testing may provide additional diagnostic and prognostic information, with exercise-induced arrhythmias, an abnormal blood pressure response and an inducible LVOT gradient, all features of HCM which may be unmasked with stress . Cardiopwith HCM . Howeverwith HCM . Exerciswith HCM , 120. Mewith HCM . If therwith HCM .There is increasing clinical interest to improve the non-invasive phenotyping of cardiovascular diseases down to the tissue and cellular levels, and at faster speed. Recent advances in metabolic imaging using phosphorus magnetic resonance spectroscopy at ultra-high field strengths (e.g. 7-T) and hyperpolarized MRI have allowed unprecedented new insights into physiological and pathological changes in cardiac metabolism , 123••. Artificial intelligence (AI) and machine learning (ML) approaches are growing rapidly in the field of MRI and are expected to change clinical practice, with particular promise in improving both image acquisition and post-processing times. Automated ML analysis using neural networks has recently been shown to achieve similar precision to human experts in CMR image processing, but at a fraction of the time cost •. This mFinally, there is active research into ‘fast’ MRI scans, with the expectation that this will translate into improved cost-effectiveness. Fast multi-slice sequences yield excellent LGE image quality for the assessment of myocardial fibrosis at significantly reduced scan time compared with conventional methods , while mIdentification of the underlying aetiology of LVH remains a challenging but important clinical problem, with significant therapeutic and prognostic implications. Recent novel CMR advances such as parametric mapping, DTI and strain, in combination with detailed morphological imaging and late gadolinium enhancement, have greatly improved our ability to non-invasively and comprehensively evaluate LVH phenotypes. CMR provides important guidance on diagnosis, therapy and prognosis, and is recommended for the differentiation and clinical assessment of patients with LVH.