Epicardial adipose tissue (EAT) contributes to atrial fibrillation (AF). However, its impact on the efficacy of left atrial posterior wall isolation (LAPWI) is unclear.Forty‐four nonparoxysmal AF patients underwent LAPWI after pulmonary vein isolation. EAT overlap on LAPWI was assessed by fusing computed tomography images with electro‐anatomical mapping.3, respectively. No differences were found between the AF‐free and AF‐recurrent groups regarding EAT volume. The EAT overlaps on LAPWI lines and LAPWI area were 1.2 ± 1.0 and 0.5 ± 0.9 cm2 respectively. Although no difference was found between groups regarding the EAT overlap on LAPWI area, the AF‐free group had a significantly larger EAT overlap on LAPWI lines . Multivariate analysis identified EAT overlap on LAPWI lines as an independent predictor of AF recurrence . Kaplan‐Meier analysis revealed that, during follow‐up, 92% of the large EAT overlap group (≥1.0 cm2) and 58% of the small EAT overlap group (<1.0 cm2) remained AF‐free (P = .008).During the 21 ± 7 months of follow‐up, AF recurred in 10 patients (23%). The total and left atrial EAT volumes were 113 ± 36 and 33 ± 12 cmEAT overlap on LAPWI lines is related to a high AF freedom rate. Direct radiofrequency application to EAT overlap may be necessary to suppress AF.  The local effect involves adipocyte infiltration into the atrial myocardiumPrevious studies22.1The present study retrospectively analyzed consecutive patients with persistent and long‐standing persistent AF who underwent catheter ablation at the Toyama University Hospital  from November 2015 to October 2016. Persistent AF was defined as AF lasting ≥7 days but <1 year, whereas long‐standing persistent AF was defined as continuous AF lasting ≥1 year. Patients with previous ablation, prior heart surgery, thyroid diseases, renal dysfunction, and contrast allergy were excluded. Overall, 44 patients were enrolled . Clinical characteristics were obtained from the patients’ medical records. The study protocol was approved by the Research and Ethics Committee of the University of Toyama  and conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent.2.2All antiarrhythmic drugs were discontinued for at least five half‐lives, and no patient received oral amiodarone prior to ablation. Sheath introducers were inserted through the right femoral vein under sedation. A transseptal procedure was performed, and two 8‐F SL0 sheaths and a steerable sheath  were advanced into the left atrium. Three‐dimensional (3D) atrial geometry was created on the NavX system  using 7‐F decapolar circular catheters . An irrigated tip radiofrequency catheter  was used for the radiofrequency application. Pulmonary vein isolation (PVI) was performed under the guidance of two 7‐F decapolar circular catheters (Lasso and Libero) positioned at the ipsilateral pulmonary vein ostia.Sequential contact mapping was performed following PVI during AF. A 7‐F decapolar circular catheter (Libero) was used for mapping. The contact of the mapping catheter was validated both by electrogram stability and by the distance to the atrial geometry surface and catheter motion, concordant with the cardiac silhouette on fluoroscopy. Analyses of complex fractionated atrial electrograms (CFAEs) were performed in 342 ± 288 points. Fractionation analyses were performed on the NavX system for CFAE mapping. CFAE mapping was performed with the following settings: peak‐to‐peak sensitivity, 0.04 mV; electrogram refractory period, 30 ms; electrogram width, <10 ms; electrogram segment length, 5 seconds.Following contact mapping, LAPWI was performed by creating a left atrial roof line at the most cranial aspect and a floor line joining the most inferior margin of the PVI line. If the left atrial posterior wall was not isolated, additional radiofrequency applications were performed, targeting the earliest activation site on the isolation lines. The entrance block was confirmed by voltage mapping using a 3D mapping system. The exit block was confirmed after external cardioversion using high output pacing within the LAPWI lines. The procedure was completed with the creation of a block line on the mitral isthmus and the cavotricuspid isthmus. The low voltage areas and CFAE areas were not ablated. Each radiofrequency application was performed for 30‐50 seconds. The temperature and power were maintained at 42°C and 30 W, respectively; a maximum power of 25 W was used while delivering energy to the sites near the esophagus.2.3All patients underwent contrast‐enhanced multidetector computed tomography (CT), which was performed using either a dual source 128‐slice multidetector CT‐scanner  or a 64‐slice multidetector CT‐scanner  within 3 days prior to ablation. Images were captured during a breath hold at full expiration using cardiac gating from the aortic arch's caudal aspect, through the cranial aspect of the left hemidiaphragm. The slice was 0.6‐mm thick, and a reconstructed series in systole  was selected for analysis.2.4EAT was retrospectively assessed using both visualization and an analysis software , detected by assigning Hounsfield units from −50 to −200,2.5All patients were subjected to a clinical interview and a surface 12‐lead electrocardiogram on the day after ablation and thereafter during the monthly visits to the outpatient clinic. Twenty‐four‐hour Holter monitoring was performed on the day following catheter ablation and as needed thereafter the follow‐up period. AF recurrence was identified both from the symptoms along with documentation of an AF episode lasting ≥30 seconds, on a surface 12‐lead electrocardiogram or Holter monitoring after a 3‐month blanking period from ablation. Antiarrhythmic drugs were resumed at the responsible physician's discretion.2.6t‐test, whereas categorical variables were compared using the χ2 test. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify AF recurrence predictors. Related factors with a P < .100 in the univariate analysis were selected as independent variables for multivariate analysis. Upon observing a significant correlation between two variables, the variable with lower significance was excluded from the multivariate analysis to eliminate the multicollinearity. Correlations between parameters were analyzed using the Pearson's correlation coefficient. Receiver operating characteristic curve analyses were performed to determine the optimal parameter cut‐off values for AF recurrence prediction. The outcome of ablation over time was plotted using a Kaplan‐Meier survival curve and compared between parameter groups (below vs above cut‐off) by log‐rank test. A P < .050 (two‐tailed) was accepted as statistically significant for all tests.Results are presented as the mean ± standard deviation and 95% confidence intervals. Continuous variables were compared using the unpaired Student's 33.12. The mean AF duration was 16 ± 21 months and 41% of the patients had long‐standing persistent AF. Structural heart disease and congestive heart failure were observed in 32% and 20% of patients respectively. Prior to ablation, antiarrhythmic drugs were administered in only 11% of the patients. The left atrium was enlarged, and the left atrial appendage flow velocity was below the normal range. The left ventricular ejection function was preserved and the total and left atrial EAT volumes were 113 ± 36 and 33 ± 12 cm3 respectively.Patients’ characteristics are shown in Table 2, and the LAPWI area was 11 ± 4 cm2. The total radiofrequency time was 66 ± 16 minutes, and the radiofrequency application time needed for LAPWI was 8 ± 5 minutes. The low voltage areas observed in the left atrium and posterior wall were 57 ± 21 and 10 ± 5 cm2 respectively. The CFAE areas observed in the left atrium and posterior wall were 31 ± 17 and 2 ± 3 cm2 respectively.LAPWI was successfully performed in 44 patients (100%). Mitral isthmus block and cavotricuspid isthmus block were achieved in 40 patients (91%) and 44 patients (100%) respectively. Catheter ablation data are shown in Table 2 respectively. Moreover, EAT overlaps on LAPWI lines and LAPWI area were 1.2 ± 1.0 and 0.5 ± 0.9 cm2 respectively. No significant correlations were found between the EAT overlap on the LAPWI area and the low voltage area or the CFAE area on the posterior wall .EAT overlap data are shown in Table 3.2AF recurred in 10 patients (23%) during 21 ± 7 months of follow‐up. Accordingly, the study subjects were divided into an AF‐free group (n = 34 patients) and an AF‐recurrent group (n = 10 patients).No significant differences were found between groups regarding the patients’ characteristics, including the rate of administration of antiarrhythmic drugs after catheter ablation, EAT volume Table . Regardi2, P = .029). Moreover, although the EAT overlap on LAPWI area was not different between groups, the EAT overlap on LAPWI lines was significantly larger in the AF‐free group than in the AF‐recurrent group .No significant differences were found between groups regarding EAT overlaps on PVI lines, floor line, and mitral isthmus line Table ; howeverP = .025).Univariate Cox regression analysis identified the left ventricular ejection fraction, total radiofrequency application time, and EAT overlap on LAPWI lines as factors for multivariate analysis Table . Consequ2). The difference between groups in AF‐free survival stratified by EAT overlap on LAPWI lines cut‐off of 1.0 cm2 was assessed using Kaplan‐Meier analysis  remained AF free compared to only 58% of the small EAT overlap group  during follow‐up (P = .008).In the receiver operating characteristic curve analysis, the EAT overlap on LAPWI lines yielded an area under the curve of 0.756 for prediction of AF recurrence  EAT volume was not associated with AF recurrence after catheter ablation; (b) EAT overlap on the LAPWI area did not correlate with low voltage area or with CFAE area on the posterior wall; (c) Although EAT overlap on the LAPWI area was not related to AF recurrence, large EAT overlap on LAPWI ablation lines was associated with a high AF freedom rate after catheter ablation.The local effect of EAT is partly demonstrated by the direct adipocyte infiltration into the underlying atrial myocardium. A previous experimental study using an ovine model revealed that obesity caused EAT accumulation with pronounced myocardial infiltration by adipocytes, particularly over the left atrial posterior wall.EAT also exerts a remote effect on the atrial myocardium, which arises from the systemic secretion of adipokines and metabolites. For instance, increased leptin levels can lead to increased aldosterone secretion, endothelial dysfunction, increased vascular stiffness, hypertension, and cardiac hypertrophy, all of which could contribute for AF pathogenesis.Another potential mechanism underlying the remote effect involves the fact that EAT contains ganglion plexuses, which play a critical role for AF initiation and perpetuation.The findings of the present study suggest that the AF‐promoting effect of EAT is mediated mainly by the remote effect. If the local effect comprised the main pathway underlying EAT promoting AF recurrence, then EAT overlap on the LAPWI area should be related to AF recurrence after ablation. Previous studies reported the effectiveness of catheter ablation to target areas overlapped with EAT.4.1The results from the present study show that creating LAPWI lines to cross the EAT overlap area may be critical to increase the effectiveness. Moreover, the occurrence of EAT overlap areas within LAPWI may imply that additional radiofrequency applications directly to those areas may effectively suppress AF. Previous studies have shown an association between EAT volume and AF recurrence after PVI.4.2The present study was limited in several ways. First, the number of patients was too small to draw definite conclusions. Second, the present study included only patients who underwent LAPWI. Thus, it is unclear whether the impact of EAT overlap on AF recurrence can be observed in other ablation strategies. Third, we used a decapolar circular catheter (Libero) for the voltage and CFAE mapping, whereas using a dedicated mapping catheter with a short interelectrode distance could have allowed more detailed recordings of local electrograms. Fourth, AF recurrence was evaluated using surface electrocardiograms and 24‐h Holter monitoring. Accordingly, asymptomatic AF recurrences may have been overlooked in the present study. An implantable loop‐recorder may reveal a more accurate AF‐recurrence rate. Fifth, although previous studies revealed that a radiofrequency application from atrial endocardium modified the ganglion plexuses,5Although EAT overlap on LAPWI did not relate to AF recurrence, large EAT overlap on the LAPWI ablation lines was associated with high AF freedom rate after catheter ablation. This suggests that the AF‐promoting effect of EAT is more mediated by the remote effect than by the local effect. Therefore, direct radiofrequency application to EAT overlap may be necessary for AF suppression.Authors declare no Conflict of Interests for this article.


Permeabilized cardiac myocyte preparations were attached between a force transducer and a position motor, and both the Ca2+ dependence and sarcomere length (SL) dependence of force, rate of force, loaded shortening, and power output were measured at 15 ± 1°C. The myocyte preparation size was similar between groups . The maximal Ca2+-activated isometric force was also similar between groups , which implicates that previously reported force declines in multi-cellular preparations reflect, at least in part, tissue remodeling. Maximal force development rates were also similar between groups , and both groups exhibited similar Ca2+ activation dependence of ktr values. Human cardiac myocyte preparations exhibited a Ca2+ activation dependence of loaded shortening and power output. The peak power output normalized to isometric force (PNPO) decreased by ∼12% from maximal Ca2+ to half-maximal Ca2+ activations in both groups. Interestingly, the SL dependence of PNPO was diminished in failing myocyte preparations. During sub-maximal Ca2+ activation, a reduction in SL from ∼2.25 to ∼1.95 μm caused a ∼26% decline in PNPO in donor myocytes but only an ∼11% change in failing myocytes. These results suggest that altered length-dependent regulation of myofilament function impairs ventricular performance in failing human hearts.Heart failure (HF) often includes changes in myocardial contractile function. This study addressed the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of contractile properties was measured in cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor ( Human heart failure is defined as the inability of the cardiac pump function to meet peripheral demands. Heart failure afflicts ∼6 million patients in the US and is associated with 1 in 9 deaths . Most cuThe etiology of human heart failure is complex and encompasses ventricular remodeling and alterations to cardiac myocyte biology, which include energetic deficiencies and alterations in calcium handling and myofilament function. The purpose of this study was to address the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of steady-state and dynamic contractile properties was measured in single permeabilized cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor and failing human hearts.Samples were obtained from patients undergoing heart transplants at the University of Kentucky and from organ donors who did not have heart failure. Hearts were handed to a researcher as soon as these were excised from the body. Mid-wall myocardial samples of distal anterior left ventricular free wall were dissected and snap frozen in liquid nitrogen and stored at -150°C before shipping to the University of Missouri. All procedures were approved by the University of Kentucky Institutional Review Board, and written informed consent was obtained from each patient who had heart failure and from a legally authorized representative of each organ donor. Samples were obtained from seven organ donors , four patients with ischemic heart failure , and four patients with non-ischemic heart failure . Data are presented as two groups, donor and heart failure (HF).2+ activations at long (∼2.25 μm) and short sarcomere lengths (∼1.95 μm), which are thought to span the sarcomere working range  following a slack-restretch maneuver were determined by fitting a single exponential function to the force recovery profile using the equationForce redevelopment kinetics . Velocity of shortening at any given time, t, was determined as the slope of the tangent to the fitted curve at that time point. In this study, loaded shortening velocities were calculated at time equal to 100 ms after the onset of the force clamp.where L is cell length at time Hyperbolic force-velocity curves were fit to the relative force-velocity data using the Hill equation o is the maximal isometric force, and a and b are constants with dimensions of force and velocity, respectively. Force-velocity data were normalized to isometric force to illustrate condition effects on loaded shortening velocity. Power-load curves were obtained by multiplying force x velocity at each relative load on the force-velocity curve, and statistical analysis compared peak normalized power output (PNPO) values, which were obtained by multiplying relative force at optimum power x velocity at optimum power. Curve fitting was performed using a customized program written in QBasic, as well as commercial software (SigmaPlot).where P is force during shortening at velocity V, Ppost-hoc analyses were performed using Tukey-Kramer corrections. P < 0.05 was accepted as a statistically significant difference. N = number of hearts. n = number of cardiac myocyte preparations. Values are expressed as means ± SEM.The experimental data were analyzed in SAS 9.1.3  using linear mixed effects. As previously described , this st–2) (Permeabilized human cardiac myocyte preparations were similar in size between donor and heart failure groups . At sarc–2) .2+-activated tension was similar between donor and heart failure cardiac myocyte preparations  .Maximal Ca kN⋅m–2) . For all kN⋅m–2) , the finktr) were also similar between donor and heart failure groups Donor: ktr = 0.60 ± 0.05 s–1; HF: ktr = 0.55 ± 0.04 s–1)   compared with those at long SL during sub-maximal Ca2+ activations (p < 0.001).Maximal rates of force development  . All hum< 0.001) . In addi–1; HF: 1.07 ± 0.14 μW⋅mg–1) . This indicates that normalized power falls further as sarcomere length is reduced in cells from organ donors than it does in cells from patients who had heart failure.The maximal absolute power generating capacity was similar between donor and heart failure groups (donor: 1.23 ± 0.15 μW⋅mgμW⋅mg–1) . Statist failure . At sub-2+-activated tension or ktr values between sexes in cardiac myocyte preparations from donor or heart failure samples , a protein that resides in the C-zone of thick filaments and the phosphorylation state is depressed in failing myocardium  decreased β-adrenergic responsiveness, (ii) depressed force-frequency relations, and (iii) slowed relaxation rates (i) increased Ca2+ sensitivity of force, (ii) depressed length dependence of the Ca2+ sensitivity of force, and (iii) decreased PKA phosphorylation of myofilament proteins. One parameter that has yielded mixed results, especially between permeabilized multi-cellular and single-cell preparations, is maximal Ca2+-activated tension. In this regard, a recent study showed depressed force and power in multi-cellular preparations obtained from the transmural region of the left ventricular free wall of human failing myocardium  may exclude populations with, for instance, diminished maximum tension-generating capacity. The preparation selection process increases the possibility of a false-negative result about tension generation capacity. Fifth, the labor-intensive nature of single cardiac myocyte contractile property measurements limits the sample size, which in combination with regional variability , diseaseThis study provides a comprehensive assessment of contractile properties of human single permeabilized cardiac myocytes from donor and patients who have heart failure. The study implicates myocardial tissue remodeling to explain, at least in part, previous reports of depressed force and mechanics in human multi-cellular myocardial preparations. Additionally, since the sarcomere length dependence of power was diminished in myofilaments from failing hearts, it is likely that that altered length dependence of myofilament power contributes to the depressed Frank-Starling relationship in failing human hearts. Future exploration of unique molecular mechanisms will necessitate next-generation, unbiased, cellular functional proteomic approaches on preparations that had their mechanics measured. Additional work is needed to address other myofilament properties, including dynamic response to calcium transients, myofilament efficiency, thin and thick filament dynamics, and relaxation kinetics, and how these are affected during the progression to heart failure. Future investigations will also require systematic delineation of how confounders such as genetics, disease etiology, environment, age, sex, co-morbidities, and medications affect myofilament function studies. Both the expansion of dynamic myofilament studies and critical evaluation of individual patient scenarios are necessary for future, best-practice precision medicine to treat the underlying molecular mechanisms that cause human hearts to fail.The datasets generated for this study are available on request to the corresponding author.All procedures were approved by the University of Kentucky Institutional Review Board and written informed consent was obtained from each patient who had heart failure and from a legally authorized representative of each organ donor, subjects gave informed consent.KM, LH, and JR performed human single cardiac myocyte preparation experiments. MG and KC procured human tissue. KM, LH, JR, MG, and KC contributed to data analysis and manuscript preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hemodynamics quantification is critically useful for accurate and early diagnosis, but we still lack proper diagnosticmethods for many cardiovascular diseases. Furthermore, as most interventions intend to recover the healthy condition, the ability to monitor and predict hemodynamics following interventions can have significant impacts on saving lives. Predictive methods are rare, enabling prediction of effects of interventions, allowing timely and personalized interventions and helping critical clinical decision making about life-threatening risks based on quantitative data. In this study, an innovative non-invasive imaged-based patient-specific diagnostic, monitoring and predictive tool  was developed, enabling quantifying (1) details of physiological flow and pressures through the heart and circulatory system; (2) heart function metrics. C3VI-CMF also predicts the breakdown of the effects of each disease constituents on the heart function. Presently, neither of these can be obtained noninvasively in patients and when invasive procedures are undertaken, the collected metrics cannot be by any means as complete as the ones C3VI-CMF provides. C3VI-CMF purposefully uses a limited number of noninvasive input parameters all of which can be measured using Doppler echocardiography and sphygmomanometer. Validation of C3VI-CMF, against cardiac catheterization in forty-nine patients with complex cardiovascular diseases, showed very good agreement with the measurements. Complex valvular-vascular-ventricular interactions (C3VI) is the most general and fundamentally challenging conditionin which multiple valvular, vascular and ventricular pathologies have mechanical interactions with one another wherein physical phenomena associated with each pathology amplify effects of others on the cardiovascular system6. Examples of components of C3VI include: valvular disease , ventricular disease , vascular disease , paravalvular leaks, and LV outflow tract obstruction in patients with implanted cardiovascular devices such as transcatheter valve replacement (TVR), changes due to surgical procedures for C3VI  and etc7.Cardiovascular disease is the leading cause of death globally, taking more lives than all forms of cancer combined and is the leading cause of burden on healthcare around the world as well. It is expected to remain the first cause of death by 2030 in the world“Cardiology is flow”8. The main functions of the cardiovascular system are to transport, control and maintain blood flow in the entire body. Abnormal hemodynamics greatly alters this tranquil picture, leading to initiation and progression of disease9. These abnormalities are often manifested by disturbed fluid dynamics10 , and in many cases by an increase in the heart workload . Hemodynamicsquantification can be greatly useful for accurate and early diagnosis butwe still lack proper diagnostic methods for many cardiovascular diseases13 because the hemodynamics analysis methods that can be used as engines of new diagnostic tools are not well developed yet. Furthermore, as most interventions intend to recover the healthy condition, the ability to monitor and predict hemodynamics following particular interventions can have significant impacts on saving lives. Despite remarkable advances in medical imaging, imaging on its own is not predictive14. Predictive methods are rare. They are extensions of diagnostic methods, enabling prediction of effects of interventions, allowing timely and personalized interventions, and helping critical clinical decision makingabout life-threatening risks based on quantitative data.16. Effective diagnosis and prediction hinge on quantifications of the global hemodynamics (heart workload) and of the local hemodynamics  of the cardiovascular system as all are very important for long-term health of the heart16. However, there is no method to invasively or noninvasively quantify the heart workload  and to provide contribution breakdown of each component of the cardiovascular diseases. Moreover, current diagnostic methods are limited and cannot quantify detailed information of the flow dynamics of the circulatory system . Although all of these can provide valuable information about the patient’s state of cardiac deterioration and heart recovery, currently, clinical decisions are chiefly made based on the anatomy alone. To augment anatomical information, cardiac catheterization is used as the clinical gold standard to evaluate pressure and flow through heart and circulatory system but it is invasive, expensive, high risk and therefore not practical for diagnosis in routine daily clinical practice or serial follow-up examinations17. Most importantly, cardiac catheterization only provides access to the blood pressure in very limited regions rather than details of the physiological pulsatile flow and pressures throughout the heart and the circulatory system. Phase-contrast magnetic resonance imaging can provide flow but it has poor temporal resolution, is costly, lengthy and not possible for many patients with implanted devices19. Doppler echocardiography (DE) is potentially the most versatile tool for hemodynamics as it is low-cost and risk-free and has a high temporal resolution. Despite all DE potentials and the progresses that have been made in its clinical use, to date, there have been no DE methods to comprehensively evaluate local hemodynamics, to evaluate global hemodynamics or to breakdown contributions of each components of the cardiovascular diseases. Computational mechanics has potentials to supplement DE to fill this gap and can offer a powerful means to augment clinical measurements to create non-invasive patient-specific diagnostic and predictive methods for monitoring, treatment planning and risk assessment.The heart resides in a sophisticated vascular network whose loads impose boundary conditions on the heart functionCurrently, none of the above metrics can be obtained noninvasively in patients and when invasive procedures are undertaken, the collected metrics cannot be by any means as complete as the results that C3VI-CMF provides. C3VI-CMF uses limited input parameters all of which can be measured using DE and sphygmomanometer. The tool only uses Doppler parameters that can be reliably measured. This tool has a lumped-parameter model at its core and includes several sub-models allowing analysis of any combination of complex valvular, vascular and ventricular diseases in both pre and post intervention conditions. In this paper, we report validation of C3VI-CMF against catheterization data in forty-nine patients with C3VI.In this study, an innovative non-invasive image-based patient-specific diagnostic, monitoring and predictive computational-mechanics frameworkwas was developed for C3VI. For simplicity, this C3VI computational mechanics framework is called C3VI-CMF in this paper. This computational tool enables (1) quantifying details of the physiological pulsatile flow and pressures through the heart and circulatory system ; (2) quantifying heart function metrics, e.g., left ventricle workload . C3VI-CMF also provides the breakdown of effects of each disease constituents on the global function of the cardiovascular system. C3VI-CMF can also quantify other heart-function metrics such as the left-ventricular end-diastolic pressure and instantaneous left-ventricular pressure. in silico model of the cardiovascular system. The algorithm uses the following input parameters that all can be reliably measured using Doppler echocardiography: forward left ventricular outflow tract stroke volume, heart rate, ejection time, ascending aorta area, left ventricular outflow tract area, aortic valve effective orifice area, mitral valve effective orifice area, and grading of aortic and mitral valves regurgitation severity. These parameters are measured in the parasternal long axis, parasternal short axis, apical two-chamber, apical four-chamber, and apical five-chamber views of the heart 15 and in vivo MRI data (N = 57)22.The developed algorithm (C3VI-CMF) consists of a parameter estimation algorithm (see below) and a lumped-parameter model that includes several sub-models allowing analysis of any combination of complex valvular, vascular and ventricular diseases in both pre and post intervention conditions: 1) left atrium, 2) left ventricle, (3) aortic valve, (4) mitral valve, (5) systemic circulation, and 6) pulmonary circulation  can be normalized with respect to maximal elastance Emax, i.e., the slope of the end-systolic pressure-volume relation, giving EN(tN)=E(t)/Emax. Time then can be normalized with respect to the time to reach peak elastance, TEmax (tN = t/TEmax).Coupling between LV pressure and volume was performed through a time varying elastance E(t), a measure of cardiac muscle stiffness.24, (2) a Boltzmann Distribution25, and (3) a double Hill function27. We simulated the lumped-parameter model using these elastance functions for several different patient input parameters and found that the double Hill function model gave the most accurate  results for the pressure, flow, and volume waveforms. The use of the double Hill function was motivated by myocyte recruitment during preload, which is fundamentally a cooperative process28 and consequently, is modeled by a sigmoidal Hill function29. Both the Gaussian function and Boltzmann distribution not only gave sub-par results compared to the Hill model, but also did not model the myocyte recruitment mechanism: The Gaussian function is symmetric about a mean23, which is not correct for our model because contraction and relaxation are not symmetric processes39. The Boltzmann distribution is a probability distribution of physical states25, and hence does not capture the dynamic cooperativity of myocytes recruitment. Consequently, to model the LV normalized time-varying elastance curves (EN), we used a double Hill function as the following27:39 to obtain physiologically realistic waveforms for pressure, volume, and flow  a summation of Gaussian functions a summatn25, and  a double27; parameter values used can be found in Table 26. Specifically, LV contraction was initiated at T = 0, and LA contraction was initiated at 0.85 T26, resulting in a time delay of 0.15 T.Coupling between LA pressure and volume was performed through a time varying elastance E(t), a measure of cardiac muscle stiffness, using the same procedure as outlined above for the LV. The elastance function used for the LA is as defined in Eqs. 3Aortic valve was modeled using the net pressure gradient formulation Aortic regurgitation (AR) was modeled using the same analytical formulation as aortic stenosis as the following. AR pressure gradient is the difference between aortic pressure and LV pressure during diastole.40.Mitral valve (MV) was modeled using the analytical formulation for the net pressure gradient  was modeled using Eq. MPV as the following.MPV, tee and T are mean flow rate of the pulmonary valve, end-ejection time and cardiac cycle time period, respectively. In this study, Forward LVOT-SV is the only input flow condition which is reliable to measure using DE. QMPV, the mean flow rate of the pulmonary valve, was optimized so that the lump-parameter model could reproduce the desirable DE-measured Forward LVOT-SV.The pulmonary valve flow waveform was simulated by a rectified sine curve with duration The total systemic resistance was computed as the quotient of the average brachial pressure and the cardiac output  compared to aortic pressure (mean ~ 100 mmHg). This total systemic resistance represents the electrical equivalent resistance for all resistances in the current model. Because what the left ventricle faces is the total systemic resistance and not the individual resistances, for the sake of simplicity we considered the aortic resistance, ao) and systemic (CSAC)). Therefore, for each degree of arterial hypertension, the compliance was evaluated using an optimization scheme outlined in the patient-specific parameter estimation section.Physiologically, arterial hypertension is determined by two factors: the degree of reduction in the caliber of small arteries or arterioles with an ensuing increase in systemic vascular resistance and mean blood pressure, and the extent of reduction in the arterial compliance with a resulting increase in pulse pressure (systolic minus diastolic blood pressure). For each degree of hypertension, we fit the predicted pulse pressure to the actual pulse pressure (known by arm cuff sphygmomanometer) obtained from clinical study by adjusting compliances (aorta (CForward LVOT-SV), cardiac cycle time (T), ejection time (TEJ), EOAAV, EOAMV, AAO, ALVOT, EOAAR, EOAMR and brachial systolic and diastolic pressures measured by a sphygmomanometer. The following procedure was used to set up the patient-specific lumped-parameter model in the following sequence:The lumped-parameter model took the following patient-specific parameters as its inputs: forward left ventricular outflow tract stroke volume (1) Flow inputs: The lumped-parameter model used only one reliably measured flow parameter as an input: forward left-ventricular outflow tract stroke volume (Forward LVOT-SV)  Eq. . Forwardphy Fig. .Figure 32) Time inputs: Cardiac cycle time (T) and ejection time (TEJ) were measured using Doppler echocardiography.3) Aortic valve inputs: mentclasspt{minima4) Aortic regurgitation inputs: To model blood flow in the reverse direction , EOAAR and EOAAR can be calculated by dividing the regurgitant volume by the time-velocity integral of regurgitant flow using continuous wave Doppler. However, such a calculation does not always yield a correct EOAAR and therefore is not deemed to be reliable. Therefore, to quantify Doppler aortic regurgitant effective orifice area (EOAAR), aortic valve regurgitation was investigated using color Doppler images in both the long axis and short axis views by experienced cardiologists and graded qualitatively as either mild regurgitation , mild to moderate regurgitation , moderate to severe regurgitation , or severe regurgitation   Mitral valve inputs: To model the blood flow in the forward direction, mitral valve area was substituted into Eq.  Mitral regurgitation inputs: To model blood flow in the reverse direction , EOAMR is substituted into Eq. (MR), mitral valve regurgitation was investigated using color Doppler images in the apical four-chamber, parasternal long axis, and apical two-chamber views by experienced cardiologists and graded qualitatively as either mild regurgitation , mild to moderate regurgitation , moderate to severe regurgitation , or severe regurgitation   End systolic volume and end diastolic volume: End systolic volume (ESV) or end diastolic volume (EDV) measured using Doppler echocardiography was fed to the lumped-parameter model to adjust starting and ending volumes in the P-V loop diagram. For this purpose, the Biplane Ellipsoid model was used to calculate the instantaneous LV volume at the end of diastole and the end of systole using the following Equation.1, A2, L1, L2 and AVG (L1&L2) are LV area measured in the apical four-chamber view, LV area measured in the apical two-chamber view, LV length measured in the apical four-chamber view, LV length measured in the apical two-chamber view, and average of these two LV lengths, respectively  Left-ventricle inputs: The cardiac cycle time (T) was substituted into mentclass2pt{minim9) Left-atrium inputs: The cardiac cycle time (T) was substituted into mentclass2pt{minim10) Parameter estimation for systemic circulation: Parameters RSA, CSVC, and Caowere optimized so that the aorta pressure calculated using the model matched the patient’s systolic and diastolic brachial pressures measured using a sphygmomanometer . The initial values of these parameters are given in Table 11) Simulation execution: Please see the computational algorithm section.−6 and initial voltages and currents of capacitors and inductors were set to zero. The model was run for several cycles to reach steady state before starting the response optimization process, described below.The lumped-parameter model was analyzed numerically by creating and solving a system of ordinary differential equations in Matlab Simscape , enhanced by adding additional functions written in Matlab and Simscape. Matlab’s ode23t trapezoidal rule variable-step solver was used to solve the system of differential equations with an initial time step of 0.1 milliseconds. The convergence residual criterion was set to 1027 was used to generate a signal to model LV elastance. It was shown that this elastance formulation can correctly represent the LV function independent from its healthy and/or pathological conditions. Simulations started at the onset of isovolumic contraction. The instantaneous LV volume, V(t), was calculated using the LV pressure, PLV, and the time varying elastance  by optimizing QMPV (as detailed below). Finally, for each patient, RSA, CSVC, and Cao were optimized to fit the aorta pressure from the model to the patient systolic and diastolic pressures measured using a sphygmomanometer.A double Hill function representation of a normalized elastance curve for human adultsance Eq. . The LV PVC) on the model output variables. We, therefore, did not include these pulmonary parameters in the parameter-identification process and used the values given in Table In order to correctly simulate the conditions of the body of each patient, some of the parameters of the model were optimized so that the lumped-parameter model reproduced the physiological measurements performed in the patient. We conducted an extensive parameter sensitivity analysis that revealed negligible effects of changes in the pulmonary parameters  of Hamilton Health Sciences and St. Joseph’s Healthcare, both affiliated to McMaster University and Comité de ética de la investigación con medicamentos de Cantabria of the Hospital Universitario Marques de Valdecilla. Informed consents were obtained from all human participants. All methods and measurements were performed in accordance with the relevant guidelines and regulations including guidelines of the American College of Cardiology and American Heart Association. Doppler echocardiography data were acquired at 2 time points: pre-procedure and 90-day post procedure. The model takes the following echocardiography parameters in patients as inputs: forward left ventricular outflow tract stroke volume (Forward LVOT-SV), cardiac cycle time (T), ejection time (TEJ), EOAAV, EOAMV, AAO, ALVOT, EOAAR, EOAMR. The model also uses the brachial systolic and diastolic pressures measured by sphygmomanometer. Cardiac catheterizations were performed pre intervention. The pressure gradients computed using the algorithm were compared and validated against cardiac catheterization measurements in forty-nine patients with C3VI.Forty-nine patients with C3VI who underwent TAVR or mitral valvuloplasty (see Table All results were expressed as mean ± standard deviations (SD). Statistical analyses were performed using SigmaStat software . Normal distribution was assessed with the Shapiro-Wilk test.Our novel non-invasive image-based computational mechanics tool (C3VI-CMF), described above, was validated against cardiac catheterization in 49 human subjects as follows:The beat-to-beat pressure calculations of C3VI-CMF were compared with cardiac catheter pressure measurements in all 49 subjects. Figure 2 = 0.982; aorta: R2 = 0.933). Maximum relative errors of 4.49% and 4.33% were respectively observed in the aorta and LV pressure in all C3VI subjects, consistent with high correlations.The Peak pressures calculated by C3VI-CMF  were in close agreement with the catheter measurements  in all subjects (n = 49). Peak pressures resulted from C3VI-CMF correlated well with the catheter measurements as indicated by high coefficients of determination in Fig. The sophisticated vascular network connected to the heart, impose boundary conditions on it. As the local flow dynamics are influenced by downstream and upstream conditions, replicating correct flow and pressure conditions is critical in developing a patient-specific cardiovascular simulator. This not only gives patient-specific flow and pressure conditions to the local flow but also enables investigation of the effects of local hemodynamics on the global circulatory physiology. Investigating the details of flow and pressures in the presence of C3VI is very challenging because of the interactions between disease constituents and amplifying adverse effects of one another. Although cardiac catheterization is the gold standard for evaluating pressure and flow through the heart and circulatory system in clinics, it is invasive, expensive, and high risk and therefore not practical for diagnosis in routine daily clinical practice or serial follow-up examinations. Most importantly, cardiac catheterization only provides access to the blood pressure in very limited regions rather than details of the physiological pulsatile flow and pressures throughout the heart and the circulatory system.Pre-TAVR: severe calcific aortic stenosis, mild aortic regurgitation (AR), moderate to severe mitral regurgitation (MR) and moderate to severe concentric hypertrophy; Post-TAVR: mild to moderate paravalvular leakage, moderate to severe MR with moderate concentric hypertrophy and hypertension. Patient #2  and provide contribution breakdown of each component of the cardiovascular system. The heart workload is the integral of LV pressure and its volume change and was estimated as the area covered by the LV pressure–volume loop. This is especially crucial in C3VI because quantifications of the LV workload and its breakdown are vital to guide prioritizing interventions.C3VI-CMF was able to quantify the heart workload .Figures Figure Due to the wide inter-subject variability in cardiovascular anatomy and pathophysiology, it is ideally necessary to design individualized treatment plans based on the diagnosis data and the predictions made about individuals’ risk of the intervention. The C3VI-CMF framework developed here is an innovative patient-specific non-invasive diagnostic, monitoring, and predictive tool that can investigate and quantify effects of C3VI constituents on the heart function, and the circulatory system. The basis of C3VI-CMF is calculations of the local hemodynamics  and global hemodynamics (the heart workload). This tool can provide the breakdown of the effects of disease constituents on the global function of the heart as well so it can help predicting the effects of interventions and planning for the sequence of interventions. C3VI-CMF is capable of tracking cardiac and vascular state based on accurate time-varying models that reproduce physiological responses. While such information is vitally needed for effectively using advanced therapies to improve clinical outcomes and guiding interventions in C3VI patients, they are not currently accessible in clinic.purposefully uses reliable non-invasive input parameters to continuously calculate patient-specific hemodynamics quantities to be used for diagnosis, monitoring, and prediction of cardiac function and circulatory state with direct clinical relevance.We evaluated our method under pathophysiologic conditions and assessed its performance in forty-nine C3VI patients with a substantial inter- and intra-patient variability with a wide range of disease. The presented results demonstrate not only repeatability but also validity even in vastly different physiologic conditions Figs. ; Table 2C3VI-CMF can be potentially used as: (1) a personal wearable device or as a mobile application for patient monitoring; (2) a module incorporated in the software of Doppler echocardiography machines for diagnosis and prediction; and (3) a monitoring and diagnostic device for ambulatory care and intensive and critical care unit.This study was performed on 49 patients with C3VI. Future studies must consider further validation of C3VI-CMF in a larger population of C3VI patients.


Placing the left ventricular (LV) lead in a viable segment with the latest mechanical activation (vSOLA) may be associated with optimal cardiac resynchronization therapy (CRT) response. We assessed the role of gated SPECT myocardial perfusion imaging (gSPECT MPI) in predicting clinical outcomes at 6 months in patients submitted to CRT.Ten centers from 8 countries enrolled 195 consecutive patients. All underwent gSPECT MPI before and 6 months after CRT. The procedure was performed as per current guidelines, the operators being unaware of gSPECT MPI results. Regional LV dyssynchrony (Phase SD) and vSOLA were automatically determined using a 17 segment model. The lead was considered on-target if placed in vSOLA. The primary outcome was improvement in ≥1 of the following: ≥1 NYHA class, left ventricular ejection fraction (LVEF) by ≥5%, reduction in end-systolic volume by ≥15%, and ≥5 points in Minnesota Living With Heart Failure Questionnaire (MLHFQ).P = .007). Change in LV PSD had an AUC of 0.78 (0.66-0.90) for the primary outcome. Improvement in LV PSD of 4° resulted in the highest positive likelihood ratio of 7.4 for a favorable outcome. In 23% of the patients, the CRT lead was placed in the vSOLA, and in 42% in either this segment or in a segment within 10° of it. On-target lead placement was not significantly associated with the primary outcome .Sixteen patients died before the follow-up gSPECT MPI. The primary outcome occurred in 152 out of 179 (84.9%) cases. Mean change in LV phase standard deviation (PSD) at 6 months was 10.5°. Baseline dyssynchrony was not associated with the primary outcome. However, change in LV PSD from baseline was associated with the primary outcome  contains supplementary material, which is available to authorized users. Heart failure affects more than 15 million people worldwide and is growing globally at epidemic proportions, causing considerable increases in disability, mortality, and healthcare costs.1As a consequence of the epidemiologic transition and advances in health care, as well as the aging of the population and the high prevalence of coronary artery disease (CAD), hypertension, obesity, and diabetes mellitus are increasing and will have a significant impact on the incidence of heart failure in low-and-middle income countries. Therefore, in a few years, the incidence and prevalence of heart failure may reach similar levels to those observed in high-income countries.10Assessment of LV dyssynchrony has been approached with a number of imaging techniques, such as echocardiography with tissue Doppler imaging, strain imaging and more recently speckle-tracking; magnetic resonance imaging; gated blood pool ventriculography and gated single photon emission computed tomography (gSPECT).17LV mechanical dyssynchrony, site of latest mechanical activation, and myocardial scarring are important parameters related to CRT response.19Since many heart failure patients will undergo a gSPECT myocardial perfusion imaging (MPI) study as part of the work-up, added to the ventricular function information and the perfusion images to assess the presence, extent and location of myocardial scar or fibrotic tissue, these patients can benefit from the simple additional phase analysis to measure LV dyssynchrony. Although this knowledge may influence site selection for LV pacing lead placement, to date, there is no multicenter trial evidence to support it. Additional potential benefits for gSPECT MPI are its widespread availability, automation, and reproducibility and the ability to obtain data from already acquired gSPECT MPI studies.Therefore, the International Atomic Energy Agency (IAEA) has sponsored a non-randomized, multicenter trial: “Value of intraventricular synchronism assessment by gated-SPECT myocardial perfusion imaging in the management of heart failure patients submitted to cardiac resynchronization therapy” (IAEA VISION-CRT). The aim of this trial is to improve the clinical response of heart failure patients by properly predicting response to CRT therapy and helping guide the optimal placement of the LV lead by using nuclear medicine techniques. Here, we report our primary findings.Ten centers from 8 countries  participated in this prospective cohort study. The countries’ main investigators recorded all the data  in individual forms for each patient, and these data were collected by the central management center in the IAEA headquarters in Vienna.® was administered by study personnel and change was assessed by the conventional 5-point criteria.In each participant center, the New York Heart Association (NYHA) class was assessed by a clinical cardiologist unaware of the imaging results as determined by the core lab. Minnesota Living With Heart Failure Questionnaire (MLHFQ)Emory University (USA) acted as a core lab for centralized gSPECT MPI reconstruction, processing and phase analysis. The core lab was blinded as to each patient’s clinical and CRT information. Statistical analysis of the acquired data was carried out by the All India Institute of Medical Sciences (India).We aimed to assess the role of LV dyssynchrony and viability quantified from gSPECT MPI to predict clinical outcomes at six months in subjects undergoing CRT. Improved clinical response (primary outcome) was defined as at least one of the following 4 points at six months: improvement by at least 1 NYHA class, improvement of LVEF by ≥5%, reduction of end-systolic volume (ESV) by ≥15%, and improvement of LVEF by at least 5 points in MLHFQ.The LV lead placement was not guided by gSPECT imaging data but by the conventional clinical practice of each participating site and then the results were compared as to whether it followed the SPECT recommendation (on-target) or not. We defined lead placement as on-target or recommended as in the study by Friehling et al.The study was approved by the participant countries’ scientific councils and complies with the Declaration of Helsinki. Written informed consent was obtained from all participants and patient anonymity was maintained during data analysis.One hundred and ninety-eight patients underwent CRT, but complete data of clinical assessment, baseline core-lab SPECT and clinical six-month follow-up data were obtained in 195 patients.For the analysis, 195 sequential patients with gSPECT MPI who met the following inclusion criteria were included: stable patients over 18 years old with NYHA functional class II, III or ambulatory IV heart failure for at least three months before enrolment, despite receiving optimal tolerated medical therapy according to current guidelines; LVEF ≤ 35% from ischemic or non-ischemic causes, measured according to the usual procedure at the participating centre for inclusion, whereas LVEFs used for analysis came from nuclear core lab; intrinsic QRS duration of ≥120 ms, with morphology of left bundle branch block; sinus rhythm; written informed consent. Exclusion criteria were as follows: arrhythmias that prevented the gated acquisition; major coexisting illness affecting survival less than one year; right bundle branch block; pregnancy or breast-feeding; acute coronary syndromes, coronary artery bypass grafting or percutaneous coronary intervention in the last three months before enrolment and within six months of CRT implantation. These patients were studied by gSPECT MPI at rest within up to four weeks before the CRT implantation, and 6 ± 1 months after. As sixteen patients died between the baseline and follow-up period, 179 patients were included for the final analysis  of 99mTc-sestamibi or tetrofosmin. SPECT images were acquired on dual-headed cameras using 180° orbits and a standard resting protocol with either 8 or 16 frames ECG-gating according to standard current guidelines.Algorithms for measuring LV dyssynchronyThe position of the LV lead post-implantation was determined from postero-anterior and lateral chest radiography and localized on a 17-segment polar map of the LV by an electrophysiologist blinded to gSPECT MPI findings.α of 0.05%.For power analysis, we assumed that dyssynchrony by imaging will be present in approximately two-thirds of any patient population submitted for CRT. From previous studies, we estimated that 75% of those who have dyssynchrony on imaging will demonstrate a clinical response. Assuming that the likelihood of a favorable clinical response is reduced by 30% (to about 53%) among those who do not demonstrate dyssynchrony on imaging, we estimated that a sample size of about 180 patients would be sufficient for a power of 80% at a two-tailed Left ventricular dyssynchrony was defined as left ventricular phase histogram standard deviation (PSD) >43°,P value <.05 to be statistically significant.Lead position as recorded at the time of device implantation was categorized as on-target if it was placed in the vSOLA as identified on the SPECT study. It was considered acceptable if it was placed in segments within 10° of the last viable contracting segment. We assessed the reduction in LV dyssynchrony with lead position and determined its independent predictive value in predicting the primary outcome or its components. All analyses were performed using Stata 13 . We considered a r = .028; P = .698). Changes in the measurements of the primary endpoints are presented in Table Baseline patients’ clinical characteristics are presented in Table At six-month follow-up, the medications of the 179 living patients were as follows: beta blockers , angiotensin-converting-enzyme inhibitors , statin , aspirin , angiotensin II receptor blockers , diuretics , mineralocorticoids .P = .585).Overall, the primary outcome occurred in 152 out of 179 (84.9%) patients. Functional class improved by at least 1 NYHA class in 67% patients, improvement in LVESV by ≥15% occurred in 54% and LVEF improved by ≥5% in 47%. The MLHF score improved by ≥5 points in 76% of those for whom data were available. Sixteen patients died between the baseline and follow-up period, and thus were excluded from the analysis. Twelve out of 129 (9.3%) patients with LV dyssynchrony, defined as LV PSD > 43°, died compared to four out of 66  and PSD was >43° in 129 (66%) patients. Baseline dyssynchrony was not associated with the primary outcome in univariable  or multivariable analyses . The area under the ROC was 0.43. In 46 (23%) patients the CRT lead was placed in the last viable contracting segment, and in 84 (42%), it was placed in either this segment or in a segment that was within 10° of it. Dyssynchrony was not associated with the primary outcome among these patients.P = .007; OR = 1.04 per 1° decrease in LV PSD). Patients with on-target  or acceptable lead placement  also were associated with the primary outcome but the relationships were not statistically significant.The change in LV PSD at six months for the following categories was 10.5° for the overall population, 9.1° for on-target, and 8.8° for on-target/acceptable segments lead placement . Only nine patients had completely off-target lead placement. There was no significant relationship of an off-target lead placement with the primary outcome. Odds ratios associated with the improvement in LV dyssynchrony and occurrence of the primary outcome are shown in Table r = .367, P < .001) .The change in LV PSD correlated with a change in LV ESV from baseline  Figure . The posThe area under the ROC was 0.78 (0.66-0.90) for the association of the improvement in LV PSD with the primary outcome Figure . An imprIn this study, we found that baseline LV dyssynchrony was not associated with the primary outcome. However, an improvement in LV PSD of 4° was associated with the highest positive likelihood ratio of 7.4 for a favorable clinical outcome; then changes in LV PSD paralleled changes in the primary outcome and its components, indicating that a dyssynchrony reduction as measured by LV PSD could be associated with outcomes improvement.The fact that a 4-degree change was significant points to the strength of the discriminatory power of the change in PSD and the fact that there is no need to look for a more robust method. Moreover, the developers of the PSD method used have established that a phase difference of as low as 2.8 degrees can be detected.On the other hand, the lead placement in relation to vSOLA on-target or acceptable segments identified by gSPECT MPI did not correlate with clinical outcomes in our study.Our results are based on the study of a contemporary international multicenter population receiving standard state of the art contemporary heart failure therapy, and are comparable in terms of outcome with other heart failure similar populations who received CRT.Considering that the post hoc analysis of LV lead positioning in the MADIT-CRT cohort revealed that apical positioning, compared to basal positioning of the LV lead, results in a significant increase in heart failure events and death,It has been shown that the presence of baseline mechanical dyssynchrony measured by echo was associated with a response to resynchronization therapy.On the other hand, Naegeli et al. have shown that after successful CRT implantation, clinical long-term response (27 ± 19 months) is independent of correction of dyssynchrony measured by echocardiography parameters and QRS width. They found several other factors indicating poor outcome such as markers of poor cardiac function, diabetes and poor renal function.37In the present work, we have found that the difference between baseline and six months post-CRT dyssynchrony is a sensitive parameter of clinical outcomes, rather than the baseline value by itself. Thus, LV dyssynchrony automatically measured by PSD from gSPECT MPI is a valid marker of CRT clinical outcomes. This may have an important clinical implication because it represents a sensitive way to predict outcomes to be used in the clinical evaluation of these patients, and as far as we know, our work is the first to give a value of change of LV PSD with a high positive likelihood ratio.Bleeker et al. reported an acute improvement in LV dyssynchrony immediately after biventricular pacing, and defined this improvement as an acute phenomenon.P < .01).18Ideally, the LV lead of a CRT device would be placed at the precise location of latest electromechanical activation in a viable segment. Therefore, LV mechanical dyssynchrony, site of latest mechanical activation, and myocardial scarring are important parameters related to CRT response.Nevertheless, we did not find clinical improvement with on-target lead placement, supported by the fact that the degree of dyssynchrony was not significantly reduced in these patients. Two main potential reasons can be advocated: first, we depended on electrophysiologists to report the lead placement site, which could not have been totally exact; second, the algorithm to detect the last viable contracting segment may need further improvement. In addition to this, a third reason could be that the electrophysiologists involved in the study, although blinded to the gSPECT MPI results, received the echo information including the sites of scar if present, and this could have influenced the decision to not pace the non-viable tissue. In fact, only in 3.58% (7/195) of our patients the lead was placed in a hypoperfused non-viable segment as compared to the 19% (17/90) of the patients in the Boogers study.18P = .031) when the LV lead was guided to be positioned in vSOLA vs. a control group. Responders were identified as a ≥15% ESV reduction at six months measured by echo. They also found a higher proportion of implanted leads at a scar site 12% (24/207) with twice as many scar implantations in their control group. Moreover, the day after CRT implantation ventricular delays was optimized by echo. This is consistent with our finding that improvement in LV PSD by gSPECT MPI post CRT is a significant predictor of clinical outcomes. However, it must be noted that reliable echocardiographic measurements require expertise in order to obtain consistent and reproducible results. Automated phase analysis from gSPECT MPI has a significant impact clinically because it allows gSPECT MPI, the most widely used nuclear imaging procedure for the management of CAD, to assess cardiac dyssynchrony and heart failure.41In contrast to our results, some studies using echocardiography and speckle tracking method,The main limitation is that this trial was not designed as a randomized trial. This was necessary in order to obtain international electrophysiologists’ participation to perform implantations at their discretion using their guidelines and not be guided by the gSPECT MPI results. Thus, although all patient recruitment and analysis were done prospectively, the decision as to whether the lead was placed on target or not was determined retrospectively, albeit blinded to all results. Here the patients where the LV lead was not placed in the SPECT recommended sites acted as the control group. Another limitation of the trial is that the location of the LV lead position was provided by the electrophysiologist who placed it and this was not independently verified.LV dyssynchrony improvement by gSPECT MPI, but not on-target lead placement, predicts clinical outcomes in patients undergoing CRT. In addition, the fact that PSD change was very significant supports LV PSD as an important physiological variable associated with CRT response and further investigation is required.The fact that the change in PSD is very significant whether the lead was on-target or off-target indicates that LV PSD is an important related physiological variable associated with response to CRT. However, further investigation is required.Supplementary material 1 (PPTX 351 kb)Below is the link to the electronic supplementary material.


Cardiac involvement has been described in idiopathic inflammatory myopathies (IIM), including non-specific ECG and echocardiographic findings. Aim of our study was to evaluate myocardial deformation parameters in IIM and to correlate them with late gadolinium enhancement (LGE) findings using cardiac magnetic resonance imaging (CMR).Forty-seven consecutive patients with histologically proven IIM were included into our study. Twenty-five healthy volunteers were used as a control group. All patients and controls underwent CMR examination using a 1.5 T scanner including functional cine and LGE imaging. After a mean follow-up of 234.7 ± 79.5 days a second CMR examination was performed in IIM patients.In comparison to healthy volunteers, IIM patients had lower left ventricular mass and left ventricular global radial, circumferential and longitudinal strain. There was no significant difference in left ventricular ejection fraction.Patients with LGE (N = 28) had lower left ventricular ejection fraction (p = 0.016), global right and left ventricular longitudinal strain (p = 0.014 and p = 0.005) and global left ventricular diastolic longitudinal strain rate (p = 0.001) compared to patients without LGE (N = 19).In IIM patients, a significant decrease of left ventricular ejection fraction, left ventricular mass and all measured deformation parameters was observed between baseline and follow-up CMR.Cardiac involvement in IIM is frequent. Impairment of systolic and diastolic deformation parameters and a worsening over time can be observed. CMR is a useful tool for cardiac diagnostic work-up of these patients. Idiopathic inflammatory myopathies (IIM) are potentially treatable chronic autoimmune disorders with muscle weakness, muscle enzyme elevation, and extra-muscular manifestations , 2. TheyCardiac magnetic resonance (CMR) imaging has become the standard non-invasive imaging modality in inflammatory myocarditis  and for Patients with known and treated IIM and patients presenting with suspected inflammatory myopathy were screened for inclusion into the study. Before enrollment the diagnosis had to be histopathologically proven by skeletal muscle biopsy. CMR-Scans were performed at baseline and after a follow-up of about 6 to 9 months. A control group of healthy volunteers were screened for age and gender match.Exclusion criteria were contraindication for CMR, gadolinium-based contrast agent, pregnancy, unknown contraception or a severely reduced condition due to immobility because of severe paresis or the diagnose of inclusion body myositis. All included patients gave informed written consent. The study was approved by the local ethics committee .CMR was performed in all patients using a 1.5T scanner  with a 32-channel phased-array cardiac surface coil. For volumetric, functional, and feature tracking analysis a steady-state free precession cine sequence  in contiguous short axis orientation covering the entire left and right ventricle, and three long axis views  were obtained as previously reported , 14.For LGE imaging, gadoterate meglumine  was administered intravenously at the dose of 0.2 mmol/kg body-weight. After 10 min, a look-locker sequence for individual adjustment of the inversion time was performed in short axis orientation. Thereafter, an inversion-recovery gradient-echo sequence  for evaluation of LGE was acquired in the same orientations as the cine images , 14.All CMR images were anonymized before DICOM transfer to a dedicated workstation. Two experienced readers, blinded to the clinical data, evaluated all images in consensus using a dedicated software . Cine images were analyzed for right and left ventricular end-diastolic, end-systolic volumes, and for left ventricular myocardial mass. Ejection fractions were calculated, correspondingly. Deformation parameters were evaluated using feature tracking.The inversion-recovery gradient-echo sequence was evaluated for presence of LGE by both readers in consensus. Subepicardial and/or intramural LGE was defined as non-ischemic, whereas subendocardial and/or transmural LGE as ischemic. An example for left ventricular LGE-imaging and of the visualization of myocardial deformation of a patient with IIM is seen in Fig. t test for normally distributed variables was used. Otherwise, Mann-Whitney-U test was performed. A p-value < 0.05 was regarded to be statistically significant.All data are reported as mean value and standard deviation. In case of normally distribution in the Shapiro-Wilk test, the Student The study group consisted of 53 patients with histologically proven idiopathic inflammatory myopathy. In all these patients basline CMR After a mean follow-up of 234.7 ± 79.5 days in 47 patients, the second CMR scan could be performed. There was a loss of follow-up in 6 patients. In the study group, 10 patients had dermatomyositis, 31 had polymyositis and 6 had other subforms of IIM. Twenty-five healthy, age and gender matched volunteers underwent CMR examinations as control group. Baseline characteristics and general findings of the study and control groups are illustrated in Table 2 vs. 1.195 ± 0.31 g/ml/m2, p = 0.003). There were significant higher scores for right ventricular ejection fraction (RVEF) in the study-group than in controls .All CMR scans were performed without complications. Left ventricular function and volumes were normal in all patients . In comparison to our healthy control group, IIM patients had similar LVEF  and left and right ventricular volumes. In difference, they had a statistically reduced strain parameters, including left ventricular global radial strain (LVGRS) , left ventricular global circumferential strain (LVGCS)  and left ventricular global longitudinal strain (LVGLS) . There was also a non-significant reduction in left ventricular mass , which reaches significance when reported to the LVEDVi (left ventricular mass/LVEDVi)  and left ventricular longitudinal diastolic strain rate. There were no significant differences in other volumetric or deformation parameters , the decrease in deformation parameters including LVGRS, LVGCS, LVGLS and RVGLS was more substantial see Fig. .Fig. 2RCardiac events are a common finding in IIM patients and a major cause of mortality , 4. EarlWe used CMR feature tracking and not echo speckle tracking for the strain analysis in our trial, since CMR is the current gold standard for the evaluation of ventricular volumes, the global and regional function. This is due to its ability to image 3D volumes unaffected by the patients habitus. For this reason, CMR has a superior inter- and intraobserver variability compared to echo. It is possible but yet not proven that CMR is thereby better than echo in the question of deformation parameters. In a current study by Pryds et al. speckle tracking echocardiography and feature tracking CMR have shown a good correlation. Both methods are thereby not interchangeable at custom, since the global longitudinal strain was measured higher and the global radial and circumferential strain lower with speckle tracking echocardiography . OtherwiIn other disease entities, deformation parameters have been shown to have a high diagnostic and predictive value. Doerner and colleagues found that especially in patients with preserved left ventricular function and suspected myocarditis, left ventricular strain parameters in combination with the Lake-Louise-Criteria improve diagnostic performance. Patients with myocarditis had a significantly reduced LVGLS in comparison to healthy volunteers  [Another recent trial showed that LVGLS was the only independent predictor of functional recovery in patients with myocarditis . A high For no obvious reason we had a difference in RVEF favoring the IIM-study group. We cannot explain whether this is due to an unknown confounder or small sample size. In fact, the values were not pathological  and therinter alia, in infectious myocarditis [Another potentially important diagnostic parameter for different cardiomyopathies is presence of LGE, which is a marker of fibrosis and consequently of irreversible myocardial remodeling. It is a common finding, carditis . As prevcarditis . In our carditis . Such reIn our study cohort, a significant decrease of LVEF and all strain parameters were observed between baseline and follow-up. A recent meta-analysis could exclude a potential correlation between age and deformation parameters . Hence, The main limitation of this study is the small sample size. This is essentially due to the fact that IIM are rare diseases according to the Rare Diseases Act of 2002 of the United States. In fact, our study population is large compared to others found in literature. Another limitation is the unicentric study design. Our data should be validated in larger cohorts of multicentric studies. Furthermore, our study was not designed to examine the impact of imaging findings on clinical decision-making and patient outcome. Whether a change in immunosuppressive therapy because of MR-findings has an influence on clinical outcome should be investigated in a prospective randomized trial.Cardiac involvement in IIM was frequently identified. We have shown that CMR including LGE and feature tracking provides additional information to classical ejection fraction measurements and may improve diagnostic work-up of IIM patients in future.


Background and objectives: Non-invasive imaging of the heart has an important place in the diagnosis and management of pulmonary arterial hypertension (PAH). The aim of this study was to establish the thresholds of cardiac magnetic resonance imaging (CMRI)-derived biventricular deformation, function parameters, and levels of N-terminal pro brain natriuretic peptide (NT-proBNP) for the prediction of survival of pre-capillary pulmonary hypertension (PHprecap) patients. Materials and Methods: In total, 64 incident PHprecap cases, who underwent CMRI, were consecutively enrolled in a prospective cohort study. Patients underwent a systemic evaluation, including measurement of NT-proBNP, two-dimensional (2D) echocardiography, six-minute walk test (6MWT), CMRI with feature tracking (FT), and right-heart catheterization (RHC). Patients were divided into two groups according to one-year survival . Survival analysis was performed. Results: One-year survival was 79.6%. The distribution between age, sex, mean pulmonary artery pressure (mPAP), New York Heart Association (NYHA) functional class, and 6MWT did not differ between the groups. Survival was significantly lower in the PAH group associated with connective tissue disease (CTD-PAH), where 44% (n = 4) of patients died during the first year. Univariate analysis revealed that severely reduced right-ventricle (RV) ejection fraction (EF) <25.5%, left-ventricle global longitudinal strain (LV GLS) >−14.18%, and right pulmonary artery (RPA) relative area change (RAC) <19%, and severely increased NT-proBNP level >1738 (ng/L) indicate an increased risk of death in PHprecap patients. Conclusions: Impaired RV systolic function and LV global longitudinal strain, decrease of pulmonary artery distensibility, and CTD-PAH etiology, together with high NT-proBNP level, impair prognosis in pre-capillary PH patients. These findings are important for the risk stratification and management of pre-capillary pulmonary hypertension patients. Pulmonary hypertension (PH) is a progressive disease affecting pulmonary arteries that is associated with right-ventricular (RV) failure and bad prognosis without appropriate treatment . Howeverprecap) patients.To the best of our knowledge, the significance of CMRI-derived RV volumetric and functional parameters, together with feature tracking evaluation of biventricular deformation indices, pulmonary arterial distensibility, and specific biomarker values in pre-capillary PH during one-year follow-up, were not previously investigated. The aim of this study was to establish the thresholds of CMRI-derived biventricular deformation, function parameters, and levels of N-terminal pro brain natriuretic peptide (NT-proBNP) for the prediction of survival of pre-capillary pulmonary hypertension  61.22 ± 18.5 mmHg, pulmonary arterial wedge pressure ≤15 mmHg). Fifteen patients in total were excluded: six for co-morbidities that could affect survival, such as underlying cardiomyopathy and valvular heart disease; three for shortness of breath during CMRI examination; four for low-quality CMRI studies due to arrhythmia; two for claustrophobia. Finally, 49 patients were included in the study. The characteristics of the patients at the time of their initial visit were collected from the medical records. After the diagnosis of PHprecap, all patients underwent treatment with the specific therapy available in our country for PAH. All patients with chronic thromboembolic PH (CTEPH) were non-operable and received conservative treatment (riociguat/sildenafil). The study protocol was approved by the Regional Biomedical Research Ethics Committee (identifier (ID) No. BE-2-23). The study was registered in Protocol Registration and Results System . Informed consent was obtained from each patient. Patients underwent systemic evaluation, including measurement of NT-proBNP, two-dimensional (2D) echocardiography, six-minute walk test (6MWT), cardiac MRI with feature tracking, and right heart catheterization. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.Between November 2012 and October 2019, all 64 incident PHCardiac MRI was performed using a 1.5-T whole-body system . Image analysis was performed on an MR analysis software system . Four-chamber (4Ch) and short-axis (SA) cine images  were acqPulmonary artery distensibility is defined as the relative change in the cross-sectional artery area throughout the cardiac cycle multiplied by the pulse pressure required to induce that change. Since the main pulmonary artery pulse pressure is not readily known, the pulsatility or relative area change (RAC) is used as a surrogate marker of MPA stiffness . MaximalDelayed-enhancement images for detection of hyperenhancement were obtained ~10 min after injection of double-dose intravenous gadobutrol (0.2 mmol/kg) using a segmented inversion-recovery prepared fast gradient echo sequence. Non-ischemic LGE pattern was considered to be present if the signal intensity in the myocardium at the ventricle insertion points (VIP) or extended to the intraventricular septal was greater than or equal to that seen in the blood pool, present in two consecutive slices, and clearly present within the myocardium when compared against a matching SSFP cine image.CMR images were analyzed using a commercial feature tracking (FT) software package . Two-, three-, and four-chamber and short-axis cine images were uploaded into the software and were used for the analysis of both ventricle longitudinal and LV circumferential strain and strain rate analysis. FT analysis was done semi-automatically by delineating the endocardial surfaces throughout the cardiac cycle. The contours were checked and manually adjusted if needed. LV global longitudinal strain (GLS) and strain rate (GLSR) were calculated by averaging the strain curves of two-chamber, three-chamber, and four-chamber long-axis views . LV globp-value <0.05 was considered significant. A chi-square (χ2) test was used for qualitative data. Spearman’s rank correlation coefficient was used to summarize the strength and direction of a relationship between two variables. In order to assess minimally false negative and minimally false positive results with greatest accuracy, the method of the ROC (receiver operating characteristics) curve was used. There were two steps to the survival analysis: univariable and binary logistic regression analysis. Variables identified in the univariable analyses were entered into a binary logistic regression model. Proportional hazards assumptions were confirmed with a Kolmogorov-type supreme test. Hazard ratio (HR) and the difference between matched groups were expressed with 95% confidence interval (95% CI). For CMR, volumetric measurements indexed for body surface area were corrected for age and sex.Statistical analysis was performed using SPSS 22.0 package . Continuous variables were summarized by mean ± SD or median (interquartile range), as appropriate. For continuous variables, differences between the two groups were compared using the non-parametric Mann-Whitney U test. A precap fulfilled the criteria. Patients were divided into two groups according to one-year survival . The observed one-year survival from the date of enrolment was 79.6%; all patients died due to cardiopulmonary events. The distribution between age, sex, mean PA pressure, New York Heart Association (NYHA) class, and 6MWT did not differ between groups. The majority of patients  were in group 1 of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines classification of PH, with the remaining patients having chronic thromboembolic pulmonary hypertension . All patients from group 1 underwent specific treatment . All CTEPH patients included into analysis were non-operable and received medical treatment. Survival was significantly lower in the PAH group associated with connective tissue disease (patients with systemic sclerosis) (CTD-PAH), where 44% (n = 4) of patients died during the first year. In the CTD-PAH group, the odds ratio to die was found to be 5.833 (1.138–29.899). Furthermore, NT-proBNP level was significantly higher in the non-survival group (p = 0.016) . Non-ischemic LGE pattern was evaluated in 43 patients. LGE was found in 79.1% of patients (n = 34) and did not differ between the groups (80.6% (n = 29) vs. 71.4% (n = 5), p = 0.274).Clinical and demographic characteristics are shown in = 0.016) . NT-proBp = 0.039, respectively)  . Other biventricular mechanical parameters were lower in the non-survival group but did not meet statistical significance.Analysis of CMR volumetric and functional parameters demonstrated that baseline RV EF was significantly lower in the one-year non-survival group (30.5% (21.5–40.75) vs. 38.0% (31.0–46.0), ctively) . Areas octively) . LV GLS p = 0.046)  vs. 19.36% (11.48–23.79), = 0.046) . Other bUnivariate analysis  revealedTwo models were developed to predict death in one year: (1) LV global longitudinal strain; (2) RV ejection fraction in the presence of CTD-PAH .precap disease (NYHA class 3 and 4). Moreover, pulmonary hypertension associated with connective tissue disease (CTD-PAH) was associated with the worst one-year survival rate, as compared with other etiology of pre-capillary PH, and these data agree with other studies.Several studies were conducted to understand mortality rates in PAH which demonstrated that one-year survival in PAH patients ranged from 68% to 91% ,16,17,18Main prognostic parameters in PAH are based on clinical symptoms , World Health Organization (WHO) functional class, 6MWT, laboratory (NT-proBNP level), hemodynamics, and cardiopulmonary exercise testing, as well as different imaging modalities such as echocardiography or CMR . Howeverp = 0.3 and p = 0.07, respectively) in our study, possibly because of the small sample size and the heterogeneous population enrolled in the study.RV dysfunction is related to the severity of PAH and clinical status of the patient . Lewis ap = 0.046), and a cut-off of 19.075% was found to be a predictor of mortality in our patient cohort. This could be related to the fact that correct measurement of the main pulmonary artery cross-sectional area is quite difficult due to its conical shape and cardiac motion in the through-plane direction, which may result in false dilatation or contraction, and this could be the reason for the inability to find significant differences. Unlike MPA, RPA is a relatively straight tube and it is mostly affected by cardiac motion in the transversal direction, which does not result in artificial distension or constriction [CMR allows non-invasive assessment of pulmonary arterial distensibility . Severaltriction . Thus, m2, p = 0.275, respectively), but did not reach statistical significance. Ventricular interaction mediated by the interventricular septum impairs the LV’s possibility to expand, contributing to a decreased LV global longitudinal strain. In a previous study, we found a correlation between LV systolic functions and LV global longitudinal strain with RV dysfunction and poor clinical outcomes in long-term follow-up [precap cohort. The present study highlights that, even in short-term follow-up, mechanical estimates of LV strains may predict an increased risk of death in patients with PHprecap.The importance of left-ventricular parameters in patients with pulmonary hypertension was shown in numerous papers ,21,25,26Our data show that increased NT-proBNP could also be one of mortality predictors in PH. We found that patients with NT-proBNP level >1738 (ng/L) had reduced survival over one-year follow-up. Thus, our findings are in agreement with the COMPERA registry, where patients with NT-proBNP level >1400 (ng/L) meet the criteria of the high-risk group .Impaired RV systolic function, LV global longitudinal strain, decreased pulmonary artery distensibility, CTD-PAH etiology, and a high level of NT-proBNP are associated with poor prognosis in pre-capillary PH patients. These findings are important for risk stratification and management of pre-capillary pulmonary hypertension patients.The main limitation of this study was the small sample size, reflecting the uncommon occurrence of PAH. Sample heterogeneity was limited by only including patients with pre-capillary PH; however, underlying conditions still varied.


Older age , longer duration of blood transfusion , larger LV end-diastolic diameter , higher values of LA peak systolic strain , higher MV E/E′ average  and higher right ventricular systolic pressure  were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value  for prediction of PACs > 24/day. In β-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.Patients with beta-thalassemia major (β-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in β-ΤΜ patients. This prospective study included consecutive β-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 β-TM patients  were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years,  Beta-thalassemia major (β-TM) is a genetic disease characterized by a significant decrease or even absence of the β-globin chain, a component of normal hemoglobin A . RegularCardiac iron overload is the primary cause for arrhythmias in β-TM patients ,3. NeverPremature atrial contractions (PACs) are usually observed at least once, in 24 h, in individuals>50years old and are not considered clinically significant .Multi-modality imaging has a diagnostic and prognostic role in patients with cardiac arrhythmias ,8,9,10. In β-TM patients there are scarce data on the echocardiographic parameters which predict atrial arrhythmias. Thus, the current analysis aimed to identify echocardiographic parameters which are associated with PACs burden in asymptomatic β-TM patients.This prospective study included all consecutive β-ΤΜ patients, systematically transfused and chelated, who were referred from the Haematology Departments to the Cardiology Outpatient Thalassaemia Clinic for their routine annual cardiology follow-up. Exclusion criteria were systolic heart failure, known coronary artery disease, atrial fibrillation, significant mitral or aortic valvular disease, congenital heart disease, severe renal or liver dysfunction, thyroid uncontrolled disorders, electrolyte imbalance, malignancies and acute or chronic inflammation diseases. The University Ethics committee approved the study protocol . All the patients, who participated in the study, provided written informed consent.Demographic, clinical, electrocardiographic, echocardiographic, 24-h Holter monitoring parameters, blood samples for hemoglobin, urea, creatinine, ferritin, bilirubin , lactate dehydrogenase and cardiac magnetic resonance (CMR) T2* assessment were prospectively recorded. All the tests were performed within 3 days before the blood transfusion.Comprehensive 2-dimensional and Doppler transthoracic echocardiography was performed with a commercially available ultrasound system  equipped with 3.5 MHz or M5S transducers. Data were stored digitally and analyzed offline on a dedicated workstation . All echocardiographic exams were performed by an experienced cardiologist, echocardiography specialist.3− (LVEDD)3]} +0.6) g; where LVEDD is left ventricular end-diastolic diameter, PWTd is posterior wall thickness in diastole, SWTd is septal wall thickness in diastole [LV dimensions were measured on the parasternal long-axis view and LV mass was estimated according to the formula by Devereux et al. (0.8 × {1.04 [(LVEDD +PWTd+ SWTd)diastole . LV massdiastole . Relativdiastole . Left vediastole . Right vdiastole . Right vdiastole . Right adiastole . Right vdiastole .Stroke volume index was calculated by multiplying the LV outflow tract cross sectional area by the velocity time integral derived from the pulsed wave Doppler recordings acquired at that point, and then indexed to body surface area . CardiacFor the strain imaging based on speckle tracking echocardiography, the apical four-, two- and three-chamber views, not foreshortened and with stable frame rate, were analyzed in each patient. Aortic valve closure time was manually defined. After tracing the LV endocardial border and adjusting the region of interest to cover only the LV myocardium in apical four-, two- and three-chamber view, the system automatically calculated LV global longitudinal strain . The peaAll patients were scanned on a 1.5Tesla MRI scanner . MyocardAll patients who were enrolled in the study underwent 24-hour Holter monitoring . Minimum, maximum and average heart rate per 24-hourswere recorded. Beats were characterized as normal, premature atrial ectopic beats and premature ventricular ectopic beats. Episodes of supraventricular tachycardias, atrial fibrillation, non-sustained ventricular tachycardias, bigeminy, couplets and triplets were recorded. The patients were divided in 2 groups, according to the median value of PACs(24/day), which was equal to the mean, as there was a normal distribution.X2) test. Comparisons for continuous variables between subgroups of participants with PACs ≤ 24/day and PACs > 24/day, were performed with the independent Student’s t-test, if normally distributed, and with Mann–Whitney U test, if non-normally distributed. Univariate analysis was performed with binary logistic regression analysis and the odds ratio (OR) and 95% confidence interval (CI) were calculated and reported. The variables with a p < 0.1 were introduced in the multivariable model. Several multivariate models were created, each of them included only 2 parameters to avoid model overfit due to the relatively small number of events. The relative fit of each model was calculated with the −2 log likelihood and compared with the chi-square (2x).Receiver operating characteristic analysis was used to assess the value of LA peak systolic strain in predicting PACs > 24 in a 24-hour Holter recording, according to the Youden’s index (Sensitivity+Specificity−1), the sensitivity, the specificity and the area under the curve [Continuous variables are expressed as mean ± standard deviation, if normally distributed and as median (interquartile range) if non-normally distributed. Categorical variables were expressed as frequencies (percentage) and were compared with the chi-square .Two-tailed n = 25) and PACs > 24/day (n = 25).A total of 50 β-ΤΜ patients were prospectively included and divided in two groups according to the median number of premature atrial complexes; PACs ≤ 24/day (p = 0.002) and were transfused for a longer period of time  compared to patients with PACs ≤ 24/day. In terms of biochemical parameters, the two groups were comparable. The 24-hour rape recordings revealed premature ventricular contractions but no ventricular tachycardia and no atrial fibrillation episodes. Only 4 patients were on medications that could reduce the presence of PACs , but they still had PACs > 24/day and thus they were included in the analysis.The clinical, biochemical and 24-hour tape parameters of the 2 groups of patients are presented in p = 0.04), impaired LA function , higher LV diastolic pressure based on mitral valve E/E′ ratio , higher tricuspid regurgitation maximal velocity  and higher estimated pulmonary artery systolic pressure  compared to their counterparts. All other echocardiographic parameters did not significantly differ between subgroups. CMR T2* values did not differ between the two groups.The cardiac imaging parameters of the 2 groups of patients are presented in p = 0.007) and duration of blood transfusion in years  were associated with PACs > 24/day  (p = 0.13). LA peak systolic strain and right ventricular systolic pressure are the only two echocardiographic parameters independently associated with PACs>24/day after adjusting for CMR T2* (Univariable association of echocardiography and CMR T2* parameters with PACs > 24/day in β-TM patients is shown in = 0.008)  but not  CMR T2* . The mod CMR T2* .p = 0.03).Among the multivariable models including the duration of blood transfusion in years and the mean heart rate of the 24-hour tape or the CMR T2* or the right ventricular systolic pressure or the LA peak systolic strain, the model including the duration of blood transfusion and the LA peak systolic strain was the most closely associated with PACs > 24/day . Of note, for prediction of PACs > 24/day .  0.002). .The present study demonstrated that in β-TM patients, LA peak systolic strain was independently associated with the frequency of PACs/day after adjustment for the duration of blood transfusions or CMR T2*. Furthermore, LA peak systolic strain ≤ 31.5% was suggested as a clinical tool to predict PACs > 24/day  in these patients.Cardiac arrhythmias in β-TM patients are induced through a multifactorial mechanism ,21,22. TAlthough PACs were initially considered to be benign and of low clinical significance , recent Engle et al. observed 39 β-TM patients and found that 19 patients had atrial arrhythmias , 12 had ventricular premature beats and 3 patients had ventricular tachycardia . In linep = 0.086).Kirk et al. showed that myocardial T2* in β-TM patients may predict the development of arrhythmias, due to myocardial iron overload . Within Changes in LA peak systolic strain have been observed in patients with hypertension, atrial fibrillation and LV diastolic dysfunction ,26,27,28In terms of arrhythmias, LA peak systolic strain has been studied principally in atrial fibrillation, where it was demonstrated to have a prognostic role ,31. ShaiThe main limitation of this prospective study is the relatively smallcohort. However, this is a robust population of adult patients with β-TM, which is a rare fatal disease. Another limitation is that the Holter recording was only for 24 h. Additionally, no data regarding the evolution of PACs over time are provided. Thus, there is no further information of whether these patients will develop atrial fibrillation in the future. Finally, we did not repeat the echocardiography to check for any changes regarding LA strain over time. The CMR data available are restricted to the T2*.In β-TM patients, LA peak systolic strain, an echocardiographic parameter indicative of LA function, is independently associated with the daily burden of PACs/day, an expression of atrial ectopic burden. All β-TM patients are followed up annually by echocardiography, thus LA strain could be used as a marker of atrial arrhythmia, resulting in rhythm monitoring with a 24-hour tape and closer follow-up of the patients with impaired LA strain. Further studies are needed to validate the role of LA strain in these patients and to elucidate its clinical significance and relation with the development of overt atrial arrhythmias.