Biventricular (Biv) pacemaker echo optimization has been shown to improve cardiac output however is not routinely used due to its complexity. We investigated the role of a simple method involving computerized pre-ejection time (PEP) assessment by radial artery tonometry in guiding Biv pacemaker optimization.Blinded echo and radial artery tonometry were performed simultaneously in 37 patients, age 69.1 ± 12.8 years, left ventricular (LV) ejection fraction (EF) 33 ± 10%, during Biv pacemaker optimization. Effect of optimization on echo derived velocity time integral (VTI), ejection time (ET), myocardial performance index (MPI), radial artery tonometry derived PEP and echo-radial artery tonometry derived PEP/VTI and PEP/ET indices was evaluated.Significant improvement post optimization was achieved in LV ET , LV VTI  and MPI  and in PEP , PEP/ET , and PEP/VTI . The correlation between comprehensive echo Doppler and radial artery tonometry-PEP guided optimal atrioventricular delay (AVD) and optimal interventricular delay (VVD) was 0.75 (p < 0.001) and 0.69 (p < 0.001) respectively. In 29 patients with follow up assessment, New York Heart Association (NYHA) class reduced from 2.5 ± 0.8 to 2.0 ± 0.9 (p = 0.004) at 1.8 ± 1.4 months.An acute shortening of PEP by radial artery tonometry occurs post Biv pacemaker optimization and correlates with improvement in hemodynamics by echo Doppler and may provide a cost-efficient approach to assist with Biv pacemaker echo optimization. Prolongation of the pre-ejection period (PEP) and shortening of ejection time (ET) is the principal abnormality in systolic heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) . PEP is Cardiac resynchronization therapy (CRT) also referred to as atrial-synchronous biventricular (Biv) pacing, has been an effective treatment for medically refractory HF patients with ventricular dyssynchrony ,6. It isIn current practice, despite careful selection, as many as 30-40% of patients do not respond to, or even deteriorate after CRT . An impoP/dt of the radial pulse appears to be a valuable and reproducible peripheral criterion of LV systolic performance in heart failure [We have recently shown the utility of phonocardiographic S3 intensity in guiding pacemaker optimization, however the technique appears to work best in those with baseline S3 of > 5 . The max failure . In rece failure . Recent We hypothesized that PEP by radial artery tonometry may correspond with ET and VTI by echo and may be used during Biv pacemaker optimization. This study was designed to investigate the relationship of PEP measurement by radial artery tonometry with echo derived ET and LV VTI, during Biv pacemaker optimization.This study protocol was approved by the institutional review board, and all subjects signed a written informed consent before enrollment. The study group comprised of 37 patients who were referred to our center for Biv pacemaker optimization by their physicians from several practices within a 50 mile radius. All patients had sinus rhythm except 4 patients with atrial fibrillation. 21 of these patients were also included in another optimization and have been reported as part of the study group in an earlier publication . PatientNew York Heart Association (NYHA) class was assessed at baseline. Patient medication list was entered. The pacemaker was interrogated using the algorithm reported previously ,21. UndeExamination was performed using a GE vivid 7 ultrasound system , a variable frequency phased array and low frequency (2.5 MHz) transducer with conventional methods ,23. A hiCardiac chamber dimensions were obtained in end systole in the parasternal long axis view. LVEF was measured by the biplane Simpson's method . LV VTI,AVD optimization was performed first and tested in the available range of 30-300 ms. Ritter's  method wOptimal AV delay was programmed, and then VV delay adjusted at the optimal AV delay. During VVD optimization progressively increasing LV pre-excitation was tested from 5 ms to 20 ms and right ventricular pre-excitation tested from 5 ms to 20 ms. Progressively increasing LV or right ventricular pre-excitation was tested until maximum LV ejection duration was obtained. In patients with mild or more MR and measurable PAP, these were re-evaluated to ensure minimum values at optimal VVD. Mitral inflow was re-evaluated after VVD testing and AVD readjusted if required. Overall the pacemaker setting was programmed to the AVD and VVD combination exhibiting the maximum LVET, VTI, optimum FT, minimum mitral regurgitation and pulmonary artery pressure. This was called tailored-echo guided "optimal setting".® device . The sensor cartridge used in the wrist strap tonometer is the same as that used in the standard AtCor device. The only difference is that the sensor cartridge is attached to an elastic strap instead of incased in the plastic tube. Earlier comparison studies within AtCor between the standard and wrist strap tonometers showed no performance differences. These were bench tests to confirm the sensitivity and frequency response of the tonometer.Radial artery pressure waveforms were acquired using a high-fidelity pressure transducer  on the patient's wrist by an elastic band and connected to a radial artery tonometry pulse wave velocity measurement system with a simultaneously acquired 3-leads ECG signal using SphygmoCorThe radial artery waveform and ECG signals were then digitized and analyzed using a custom software program which determined the time interval from the ECG-Q wave to the foot (onset) of the corresponding radial artery waveform. To position the pressure transducer, the radial artery in each arm was palpated and the wrist with the stronger pulse was used. A pillow was placed under the arm to stabilize the wrist and the transducer was placed against the skin at the location where the operator felt the strongest signal from the pulse. The strap of tonometer was adjusted to capture a signal of adequate strength. The transducer was then left in place without having to be held by the operator and only needed minor adjustments in position during the data acquisition.Examination was carried out simultaneously with the echocardiographic evaluation beginning 5-10 beats following each pacemaker adjustment. The computer screen displayed a continuous radial artery waveform and lead-II ECG wave. When 10-seconds of consistent and high quality waveforms were displayed, a computer keystroke captured and analyzed the recordings. Approximately 10 Q- radial artery foot time intervals were averaged to produce a mean value of the PEP for each record. Quality-control information was reported simultaneously to ensure consistent quality of the recordings and obtain reliable results. PEP/ET and PEP/VTI indices were calculated based on the radial artery tonometry and echo data. The optimal pacemaker setting by radial artery tonometry was taken as the AVD and VVD with the shortest PEP.At the end of the optimization procedure the pacemaker was programmed based on the results of the online echocardiographic evaluation. NYHA class was assessed at baseline and at 1 month post optimization.Radial artery tonometry automated PEP measurements from different AVDs were randomly selected (every 3rd AVD observation) and a total of 46 PEP observations from 5 randomly selected patients were measured for intraobserver PEP variability, calculated as the difference of each observation from the averagex100. Interobserver variability was determined by difference of PEP from an average of 5 readings at baseline among 2 observers in 5 subjects. The interobserver variability of PEP was 2.2 ± 2.3% and intraobserver variability was 1 ± 1.6%.Data are presented as mean values ± standard deviation (SD). Continuous variables at baseline and post optimization were compared using paired two-tailed student's t-test. Wilcoxon signed-rank test was used for ordinally scaled parameters like NYHA and mitral regurgitation severity. Pearson correlation analyses were performed between PEP and ET and VTI and between tailored-echo and radial artery tonometry-PEP methods for optimal AVD and VVD. Values of p < 0.05 was considered statistically significant.Clinical characteristics of patients at baseline are shown in Table The shortest AVD and intrinsic AVD tested in the study subjects were 66.6 ± 35.2 ms and 239.4 ± 53.7 ms respectively during pacemaker interrogation. Baseline pacemaker settings were AVD of 160 ± 53.7 ms and LV offset of 8.4 ± 14.4 ms and optimal pacemaker settings were AVD of 150.4 ± 67.2 ms and LV offset of 3.9 ± 6.7 ms (p = NS vs. baseline). A significant individual variation was present in the change in AVD setting in each patient ranging from -180 ms to +150 ms AVD from baseline. Baseline LV offset was programmed in 14 patients and RV offset in 2 patients. LV offset was added in 5 patients and removed from 7 patients and RV offset was added in 3 patients and removed in 1 patient. VVD was 0 ms post optimization in 21 patients.An acute significant improvement was achieved post optimization in echo Doppler and radial artery tonometry measurements as shown in Table A significant correlation was found between baseline ET and radial artery tonometry derived PEP  and between baseline VTI and radial artery tonometry derived PEP . PEP by echo could be measured in 31 out of 37 study patients. This was due to difficulty in delineating onset of QRS in all patients on the ultrasound rhythm tracing. Figure We used PEP/ET and PEP/VTI as a surrogate for MPI - a validated parameter for LV systolic and diastolic function. Data on PEP/VTI, PEP/ET at baseline and optimal pacemaker settings using a combination of radial artery tonometry and echo measurements is shown in Figure Figure Radial artery tonometry derived PEP trended to be higher (258 ± 35 ms) in those class III and IV symptoms (n = 19) compared to those with NYHA class I and II symptoms . PEP was shortened to a comparable degree by pacemaker optimization in both NYHA class I-II and III-IV patients to 234 ± 42 and 236 ± 30 ms respectively.We also evaluated baseline echocardiographic findings among those with baseline NYHA class of I and II (Gp I) versus those with NYHA class III and IV (Gp II) and the data is shown in Table Patients were followed at 1.8 ± 1.4 months post optimization. 3 patients, one with severe ventricular ectopy requiring reversal to original pacemaker settings, 1 with recurrent hospitalizations for end stage renal disease and one wheelchair bound from multiple sclerosis were excluded. In 29 of the remaining 34 patients, NYHA class reduced from 2.5 ± 0.8 to 2 ± 0.9 (p = 0.003). NYHA improved in 18 (62%), did not change in 7 (24%) and deteriorated in 4 (14%) patients.The major finding of this study is that an acute PEP shortening by radial artery tonometry occurs with optimization of AVD and VVD and correlates with improvement in hemodynamics measured by echocardiography. PEP predicted optimal VVD and optimal AVD in majority of patients. Ratio of PEP with echocardiographic LV ejection parameters - ET and VTI, corresponded to MPI assessment and shortened during pacemaker optimization. Findings from our study suggest that radial artery tonometry-PEP may be used in conjunction with echo derived ET or VTI to guide AVD optimization. The shortening of PEP was more pronounced in patients with NYHA class III and IV symptoms in whom PEP should be tested as a stand-alone method to guide pacemaker optimization.While there was concordance between echo derived optimal AVD and radial artery tonometry derived PEP in majority of patients, some patients had significant discrepancy. This could be related to the use of comprehensive echo Doppler parameters to guide echo optimization compared to only PEP by radial artery tonometry. A randomized study comparing echo vs. PEP guided optimization and effect on acute and chronic improvement in cardiac structural and functional parameters would be required to compare the two techniques.MPI is preload and afterload dependent and has diagnostic and prognostic power in HF patients ,27,28. EMany different echo Doppler parameters have been used in the literature for pacemaker optimization. These include mitral inflow VTI, filling time, E/A ratio, deceleration time, aortic outflow VTI, ejection duration and MR Dp/Dt. There is variability in appropriate pacemaker settings depending on which of these echo Doppler parameters is selected. It is to be noted that in almost all earlier CRT studies echo guided pacemaker optimization was used using mitral inflow or aotic outflow method. As shown in our study, comprehensive echo Doppler optimization does have a role in the management of patients - especially non responders post CRT, however it is time consuming and requires expertise. It is therefore important to find simple non invasive methods for pacemaker optimization. Radial artery tonometry technique is a simple, non invasive, fast, reproducible method of assessing PEP that can be rapidly mastered by hospital/ECG/echo staff. It eliminates operator dependent inter observer variability inherent in many echo Doppler techniques due to operator and patient related factors. Use of PEP by radial artery tonometer needs to be tested in randomized prospective studies for its value in pacemaker optimization.Echo Doppler method of pacemaker optimization we describe is time intensive. The QRS width changes in response to AVD and VVD changes may influence PEP measurement independent of mechanical effects of pacemaker changes. We chose the optimal pacemaker settings based on results of echo evaluation. We did not use radial artery tonometry as the primary method of pacemaker optimization and this utility of the device needs to be tested against echocardiography in prospective randomized studies. Our patients' baseline pacemaker settings were in a wide range at baseline and not at "out of box settings". This is because patients had pacemaker programming performed by their treating physicians by using various methods and algorithms.Our findings indicate significant concordance among echocardiographic and radial artery tonometry methods in determining optimal AVD and VVD. The additive clinical impact of the PEP optimization approach over a conventional comprehensive hemodynamic assessment using echo-Doppler techniques during optimization as a stand-alone method needs to be addressed in future studies.Nima Taha, MD: Partial fellowship support from AtCor Medical.Jing Zhang, MD, PhD: Partial fellowship support from AtCor Medical.The sponsor did not contribute to study design, data collection, data analysis or interpretation of results and did not contribute in any way to this manuscript.Reza Rafie, MD: NoneRupesh Ranjan, MD: NoneSalima Qamruddin, MD: NoneTasneem Z Naqvi, MD: Optimization of Biventricular Pacemaker Settings - Patent PendingNT: Performed PEP data collection during optimization, measured echo data, performed data entry and analysis, JZ: Performed PEP data collection during optimization, measured echo data, performed echo and PEP data entry, RR: Performed data entry and assisted with data analysis, RR: Assisted with data analysis, SQ: Assisted with data analysis, TZN: Conceived of the study, performed echo guided pacemaker optimization, coordinated and supervised data analysis and entry, drafted and revised manuscript. All authors read and approved the final manuscript


Such looping is regarded as an essential process in cardiac morphogenesis since it brings the building blocks of the developing heart into an approximation of their definitive topographical relationships. During the past two decades, a large number of genes have been identified which play important roles in cardiac looping. However, how genetic information is physically translated into the dynamic form changes of the looping heart is still poorly understood. The oldest hypothesis of cardiac looping mechanics attributes the form changes of the heart loop  to compressive loads resulting from growth differences between the heart and the pericardial cavity. In the present study, we have tested the physical plausibility of this hypothesis, which we call the growth-induced buckling hypothesis, for the first time. Using a physical simulation model, we show that growth-induced buckling of a straight elastic rod within the confined space of a hemispherical cavity can generate the same sequence of form changes as observed in the looping embryonic heart. Our simulation experiments have furthermore shown that, under bilaterally symmetric conditions, growth-induced buckling generates left- and right-handed helices (D-/L-loops) in a 1:1 ratio, while even subtle left- or rightward displacements of the caudal end of the elastic rod at the pre-buckling state are sufficient to direct the buckling process toward the generation of only D- or L-loops, respectively. Our data are discussed with respect to observations made in biological “models.” We conclude that compressive loads resulting from unequal growth of the heart and pericardial cavity play important roles in cardiac looping. Asymmetric positioning of the venous heart pole may direct these forces toward a biased generation of D- or L-loops.The transformation of the straight embryonic heart tube into a helically wound loop is named  It has a venous inlet at its caudal pole, with which it is connected to the developing veins, and an arterial outlet at its cranial pole, with which it is connected to the aortic sac. Its dorsal wall is fixed to the dorsal wall of the embryonic pericardial cavity via a mid-sagittal tissue bridge called the dorsal mesocardium. During subsequent merging of the heart-forming fields, the initially short heart tube becomes elongated by continuous addition of new building blocks to its venous and arterial poles. The elongation of the tubular heart is accompanied (i) by the disappearance of the dorsal mesocardium, so that the tubular heart now is fixed to the wall of the embryonic pericardial cavity only at its venous  and arterial  ends; and (ii) by striking changes in the spatial configuration of the developing heart, which becomes transformed from a straight into a helically coiled tube  loops while their biologically abnormal mirror images are classified as L- (levo) loops.Helices and polarized helical perversions are handed objects, which means that they can principally exist in two form variants—so-called  Männer, . With reSince the nineteenth century, the fascination for the phenomenon of cardiac looping has centered around two main questions: (i) what factor(s) drive the bending and coiling of the embryonic heart tube; and (ii) what factor(s) are responsible for the fact that, in all vertebrate species studied so far, only the so-called D-loop configuration is normally being realized during embryonic development?During the past two decades, remarkable progress has been made in answering these two questions. A large number of genes and molecular signaling pathways have been identified which play important roles either (i) in the elongation, bending and coiling of the tubular heart or, (ii) in the determination of the handedness of heart loop configuration, suggesting that these two aspects of cardiac looping are controlled by distinct sets of factors Männer, . Howeverthe growth-induced buckling hypothesis.”The historically oldest concept of the biomechanics of cardiac looping regards the bending and helical coiling of the tubular embryonic heart as results of the continuous heart tube elongation within the confined space of the embryonic pericardial cavity His, . This viin vitro without spatial restrictions  but lack a helical shape   until the middle of the bends contact the wall of the confining drill hole. The string then buckles in a three-dimensional fashion and finally acquires the configuration of a helix . Such form behavior would correspond to the form behavior characterizing the first phase of cardiac looping  and, therefore, would be in accord with the idea that growth-induced buckling may contribute to the generation of the helical shape of the “C-shaped” heart loop. Unfortunately, we could not find an answer to the question whether spatial buckling of a drill string may also generate the complex shape of a two-handed helix representing the idealized geometrical configuration of the so-called “S-shaped” heart loop. We, therefore, decided to construct a mechanical device  with which we wanted to test whether growth-induced buckling of a straight elastic rod (representing the embryonic heart tube) within the confined space of a hemispherical cavity  can generate a sequence of form changes corresponding to cardiac looping .In view of the above-mentioned recent experimental findings, we became interested in clarifying the possible role of growth-induced buckling in cardiac looping morphogenesis. As the first step on this way, we wanted to know whether the sequence of form changes characterizing cardiac looping Figure  might coIf real or simulated cardiac looping would run under conditions of precise bilateral symmetry, the ratio of the resulting loop-enantiomorphs (D-/L-loop) is expected to be 1:1. It, therefore, has been speculated that the biologically normal ~100% preference for the D-loop enantiomorph may be caused by functional or structural asymmetries already present in the pre-looping embryo . It had a rubber hardness of 17  and, therefore, can be roughly classified as a soft object. Compared with embryonic heart loops, however, it was a relatively stiff object. Thus, the material properties of our heart-tube model did not correspond to those of real embryonic heart loops. A solid silicone rubber of Shore A hardness 17 was chosen as the best material for our heart tube model since its mechanical properties facilitated (i) the highest possible deformability combined with (ii) full reversibility of buckling-deformations. These mechanical properties minimized the risk of generating falsifying memory effects at repeated buckling tests. We should also note that the silicone rod had no lumen. This means that our model neglected the tubular structure of the embryonic heart loop. We think that this fact does not significantly alter the validity of our simulation model since the early embryonic heart is a thick-walled blood vessel that has only a slim, slit-shaped lumen, which is completely closed during contraction of its myocardial wall.The straight silicone rod was positioned along the central “cranio-caudal” axis of the model. In the straight state, only a ~136 mm long end of the rod was inside of the “pericardial” cavity while the rest (~344 mm) was outside of the cavity. Thus, we distinguished two portions of the rod: (i) an “intra-pericardial” portion, representing the embryonic heart tube; and (ii) an “extra-pericardial” portion, representing the heart fields from which new material will be added to the heart. The “cranial” end of the rod was mechanically fixed to a sledge, which was anchored on a straight, ball-bearing rail oriented along the “body” midline of the model. This facilitated exact displacements of the “cranial” end of the rod along the “cranio-caudal” axis. The “caudal” end of the rod was mechanically fixed to a sledge, which was anchored on a straight, ball-bearing rail oriented perpendicular to the “cranio-caudal” axis of the model. This facilitated exact displacements of the “caudal” pole of the rod along the “left-right” axis. At the pre-looping state (straight heart tube), the length-to-diameter ratio of our heart tube model was 5.91 (136/23 mm). This value is higher than the corresponding values found in vertebrate embryos . This means that our heart tube model was slimmer than real embryonic heart loops. The slim design was chosen since our model was stiffer than embryonic heart loop (see above). This reduced the compressive forces needed for the generation of buckling-deformations.For the simulation of the cranio-caudal growth of the heart tube, the sledge carrying the “cranial” end of the rod was gradually displaced along the rail toward the “caudal” end of the model Figures . Bilaterin vivo situation where the embryonic heart loop becomes elongated by addition of new material to its cranial as well as caudal ends  of the “intra-pericardial” portion of the silicone rod would not occur along a favored plane. This differs from cardiac looping where the bending process is consistently directed toward the ventral body wall. In order to direct the sinusoidal buckling of the “intra-pericardial” portion of the silicone rod toward the ventral wall of the “pericardial” cavity, the center axes of its “cranial” and “caudal” ends were slightly tilted toward the mid-ventral aspect of the “pericardial” cavity. These slight deviations of the center axis of the silicone rod from a linear “cranio-caudal” axis correspond to the situation found in the straight heart tube of human embryos with 7 somites  to record the buckling configurations.The first set of buckling tests was conducted to clarify whether growth-induced buckling of a straight elastic rod (representing the embryonic heart tube) in a narrow hemispherical cavity  can generate the same sequence of form changes as observed in the looping embryonic heart. These tests were conducted under bilaterally symmetric conditions (center axis of the two ends of the rod in midline position).n = 50), left- and right-handed helices occurred almost at the same ratio , left-sided, or right-sided positions (Experiment 3) during the whole buckling test. During D-looping of the embryonic vertebrate heart, however, the caudal end of the straight heart tube  does not remain in its initial position but moves continuously further to the left Murray, . We wantDuring the past 200 years, research on cardiac looping has focused on the answering of two main questions: (i) what factors drive the normal positional and morphological changes of the looping embryonic heart tube; and (ii) what factors determine its handedness? The buckling experiments conducted in the present study may help to answer both questions since they may contribute to the identification of mechanical factors involved in cardiac looping. With respect to the first question, we have found that growth-induced buckling of a straight elastic rod within the confined space of a hemispherical cavity can generate a sequence of form changes corresponding to the sequence of form changes characterizing the looping morphogenesis of the tubular heart of higher vertebrate embryos Figure . Both prAccording to the growth-induced buckling hypothesis, the looping embryonic heart tube is deformed mainly by two mechanical forces: (i) an axial compressive load, resulting from a difference in cranio-caudal growth between the heart tube and the embryonic pericardial cavity Figure ; and  or incomplete looping phenotypes show either an abnormally short heart tube within a normal-sized pericardial cavity  resulting from axial compression of the tubular heart. Our present simulation model confirmed the physical plausibility of this concept. It is a well-known fact, however, that tests on biological models, such as g Ekman, . Moreoveg Ekman, . In viewg Ekman,  could noIn vitro looping of isolated embryonic heart tubes is a planar bending process that does not generate simple or complex helical configurations  when it develops in a pericardial cavity whose ventro-lateral walls have been removed before or during the initial phase of cardiac looping.Our simulation model has shown that, in a buckling process, the emergence of simple and complex helical loop configurations depends on the presence of mechanical boundaries that passively restrict the sinusoidal bending of a continuously elongating rod or tube. Thus, if the helical deformations of the looping embryonic heart would result from a buckling process, we should expect that a curved heart tube shouldn't be able to acquire a helical shape (i) when it is removed from the pericardial cavity and cultured in vitro looping of isolated heart tubes does not produce helical heart loops (see above); and (ii) that the removal of the ventral wall of the primary pericardial cavity near the onset of looping prevents the torsion (rotation) which normally deforms the bending heart tube into a helically wound heart loop  that … may be a decisive event in determining of heart situs” but, unfortunately, did not present a concept of how this asymmetry may mechanically act in the determination of heart loop handedness. Our present simulation model demonstrates, for the first time, that the idea of a handedness-determining role of an asymmetric positioning of the venous heart pole is physically plausible in the context of helical buckling morphogenesis. Future studies are needed to clarify the biological feasibility of this concept as well as to clarify the relation between the leftward displacement of the pre-looping heart of mammalian embryos and the phenomenon of leftward jogging of the pre-looping heart of zebrafish embryos . In this case, the heart loop lost its already acquired helical shape and returned to a sinusoidal configuration , chick, quail, and mouse. It will be a challenge for the future to construct models facilitating testing of the physical plausibility of the growth-induced buckling hypothesis under more realistic conditions.A further limitation of our model is the fact that it is primarily a qualitative model, which uses elements of idealized geometrical configurations and does not include realistic material properties . Thus, the morphogenetic behavior observed in our physical model for cardiac looping is an idealized picture that cannot match exactly with the morphogenetic behavior of real embryonic hearts as observed in popular biological “models,” such as zebrafish, frog  has found that the morphogenesis of fastened tendrils of climbing plants is characterized by the same global form changes as the looping morphogenesis of embryonic hearts (Männer, intrinsic curvature driven morphogenesis” (Goriely and Tabor, We should finally emphasize that our present simulation model has confirmed only the physical plausibility of the growth-induced buckling hypothesis of cardiac looping mechanics. It is not a proof for validity of this hypothesis in real biological systems. Biological objects of the same geometrical shape can be generated by different sets of forces. Because of this phenomenon, named  Männer, . This fi Männer, . In contThe 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.


Purpose. To provide an ovine model of ventricular remodeling and reverse remodeling by creating congestive heart failure (CHF) and then treating it by implanting a left ventricular assist device (LVAD). Methods. We induced volume-overload heart failure in 2 sheep; 20 weeks later, we implanted an LVAD and assessed recovery 11 weeks thereafter. We examined changes in histologic and hemodynamic data and levels of cellular markers of CHF. Results. After CHF induction, we found increases in LV end-diastolic pressure, LV systolic and diastolic dimensions, wall thickness, left atrial diameter, and atrial natriuretic protein (ANP) and endothelin-1 (ET-1) levels; β-adrenergic receptor (BAR) and dystrophin expression decreased markedly. Biopsies confirmed LV remodeling. After LVAD support, LV systolic and diastolic dimensions, wall thickness, and mass, and ANP and ET-1 levels decreased. Histopathologic and hemodynamic markers improved, and BAR and dystrophin expression normalized. Conclusions. We describe a successful sheep model for ventricular and reverse remodeling. Congestive heart failure (CHF) is characterized by an initial cardiac insult, followed by a compensatory response that results in ventricular remodeling. At the cellular level, CHF involves myocyte hypertrophy, cell death, and replacement fibrosis. At the subcellular level, the disease causes loss of myofilaments, alterations in cytoskeletal proteins, and adrenergic desensitization. α (TNF-α), atrial natriuretic protein (ANP), B-type natriuretic peptide, beta-adrenergic receptors (BARs), and angiotensin II [For the past 2 decades, the diagnosis of heart failure has relied on noninvasive methods  and invasive tests . Variousensin II . Anotherensin II . Treatmeensin II , 15. ThePrinciples of Laboratory Animal Care  and the Guide for the Care and Use of Laboratory Animals . Our Institutional Animal Care and Use Committee approved the protocol in advance.Two male Rambouillet sheep (54 ± 4 kg) were used in this study. The animals received humane care in compliance with the To accurately mimic the clinical scenario of ventricular remodeling in heart failure, we created a volume-overload heart-failure model by destroying the chordae tendineae of each sheep's mitral valve. After 20 weeks, we implanted a Levitronix CentriMag  (1st case) and a HeartWare LVAD  (2nd case) to support the animals. After 11 weeks of LVAD support, the sheep were reexamined for evidence of myocardial recovery.We followed a standard institutional anesthesia protocol that has previously been described in detail . Each shTransthoracic echocardiography was performed to obtain baseline measurements of the left and right ventricular dimensions, left ventricular mass, ventricular wall thickness, and valve function. The baseline left ventricular end-diastolic pressure (LVEDP) was measured with a micromanometer-tip pigtail catheter  inserted via the left carotid artery. After baseline hemodynamic measurements were made, baseline endomyocardial biopsy specimens were taken from the left ventricle via a transaortic route. With the sheep in stable condition, a baseline left ventriculogram was performed to assess mitral valve function. The pigtail catheter was removed, and a reusable biopsy and retrieval forceps  were introduced into the left ventricle. Under fluoroscopic guidance, this forceps was used to grasp and cut 1 or more chordae tendineae upon forceful withdrawal, creating severe MR (3+ to 4+ Seller's grade ) Figure. This coThe Levitronix CentriMag LVAD is a sterile, single-use, disposable, and centrifugal pump. The pump's 32-mL priming volume minimizes the wetted surface area and helps to limit the need for intravenous fluids during surgery. The pump inlet is on the rotational axis of the rotor; the pump outlet is perpendicular to the inlet and tangential to the outer diameter. Both the inlet and outlet ports are standardized 3/8-inch barbed connectors for easy application to standard medical-grade 3/8-inch tubing. The blood pump design is based on magnetic-levitation motor-bearing technology that allows pumping without mechanical bearings and seals. The pump's rotor “floats” in a rotating magnetic field without mechanical contact, and an external compact digital signal processor system allows precise regulation of the rotor's speed. The pump is designed to provide flow in the range of 0.5 to 9.9 L/min.The drive console is a microprocessor-based system that includes user interface keys which provide convenient management points for pump operation; a 4-line alphanumeric display for showing the system status; alert and alarm information; 27-segment digital displays that show the pump speed and blood flow rate.The HeartWare LVAD is described in detail elsewhere . BrieflyFor implantation of the CentriMag LVAD, anesthesia was induced routinely, and hemodynamic, echocardiographic, and fluoroscopic measurements were repeated as were the endomyocardial biopsies. A left thoracotomy was then performed in the 5th intercostal space, and the left ventricular apex and descending aorta were exposed for inflow and outflow cannula placement, respectively. After 2 pledgeted, 2-0 braided polyester pursestring sutures were placed on the left ventricular apex and descending aorta, 32F inflow and 20F outflow cannulas were inserted into these 2 structures, respectively. The procedures were done on the beating heart without cardiopulmonary bypass. After the cannulas were tunneled outside the chest wall, they were connected to a centrifugal CentriMag extracorporeal LVAD, and flow was initiated at 4 L/min. Pump flow was measured throughout the study with a 10-mm flow probe  on the outflow graft cannula, and unloading of the left ventricle was adjusted according to that chamber's size. Device flow was maintained between 5 and 7 L/min. The LVAD was secured to each sheep's body with a girth strap. Postoperatively, the animals were treated the same as after the initial operation. Adjunctive esmolol infusion and diuretics were used to control tachycardia and peripheral vascular resistance/urine output, respectively. The animals were given warfarin to keep the international normalized ratio between 2.5 and 3.5.The same anesthesia and postoperative protocols were used for HeartWare implantation, which has been detailed elsewhere .Eleven weeks after placing the LVAD, we remeasured the hemodynamic, echocardiographic, and fluoroscopic variables and repeated the endomyocardial biopsies with the sheep under general anesthesia.Echocardiographic assessment was performed according to the guidelines of the American Society of Echocardiography  by an ecEndomyocardial biopsies were performed before MR creation (baseline), during the 2nd operation (week 20), and during the 3rd operation (week 31) and were evaluated with transmission electron microscopy. Macroscopic postexplant analyses of the pump were also done after termination of the study.β-adrenergic receptor, ANP, and ET-1 levels were selected as markers of heart failure and were fluorescently labeled. Fluorescence was quantified as pixel densities of specific colors in split color images, using Corel Draw  and Sigma Scan Pro software . Expression of dystrophin was quantified by Western blotting of whole tissue lysates prepared from biopsy tissues. Consequently, confocal immunofluorescence was used to obtain robust quantitative information about the number of immunoreactive signals at discrete sites within the cell.In both cases, comparison of hemodynamic, fluoroscopic, echocardiographic, histopathologic, and immunohistochemical data recorded (1) during the 1st operation and (2) immediately before pump implantation confirmed the effectiveness of the heart failure induction protocol. After the 2nd operation, both sheep recovered from anesthesia without complications and were extubated within the 1st postoperative hour. Eleven weeks after LVAD implantation, they reached the scheduled endpoint without experiencing anorexia, infection, or a neurologic disorder.The explanted pumps' interior, inflow cannula, and outflow cannula were completely free of thrombus. There was no evidence of ischemia or infarction in any of the peripheral end organs .The mean LVEDP, which was 8 ± 2 mmHg at baseline, increased to 16 ± 2 mmHg immediately after chordal disruption and to 27 ± 4 mmHg during the 2nd operation. After 11 weeks of LVAD support, the mean LVEDP measured 14 ± 2 mmHg.After the mitral chordae tendineae were disrupted, left ventriculography confirmed the presence of 2nd- to 3rd-degree MR Figures . During μm in diameter decreased by 33  ±  4% compared to baseline biopsy findings  showed a 58 ± 5% loss of myofilaments in the perinuclear region; the presence of cytoplasmic vacuoles >1.5 findings .μm in diameter decreased from 33 ± 4% to 5 ± 2%. Cardiac myocytes showed an increase in the number and size of their mitochondria  to 18 ± 3%. The percentage of cells with cytoplasmic vacuoles >1.5 chondria .Compared to baseline values, there was a marked increase in the fluorescence pixel density for ANP and ET-1 along with a reduction in BAR and dystrophin density , which iAfter 11 weeks of LVAD support, biopsy samples showed a marked decrease in fluorescence pixel density for ANP and ET-1, along with an increase in BAR and dystrophin density  which maIn our pilot study, the left ventricular diastolic and systolic dimensions increased with heart failure and decreased after LVAD support, although baseline levels were not regained after 11 weeks of LVAD support. The cardiac index and left ventricular mass were elevated during heart failure and returned to near baseline levels after 11 weeks of LVAD support. Together, these results indicated the successful development of heart failure in sheep after chordal disruption, followed by recovery after LVAD support, as determined by physical measurements and hemodynamic data.We used an adult sheep model, primarily because of the ease with which heart failure can be induced and subsequent LVAD therapy can be applied in this model. Other fundamental advantages of the sheep are the animal's size , minimal growth rate, ease of management, and hemodynamic similarities to humans. Moreover, the ability to perform sequential biopsies allowed us to monitor the progress of heart failure and to correlate the extent of remodeling and its reversal with ANP, ET-1, BAR, and dystrophin levels. Because our volume-overload heart failure ovine model was not a previously established one, biopsies to detect heart failure creation (remodeling) and postimplant recovery timing (reverse remodeling) were scheduled and performed according to the guiding results of the echocardiographic follow-up data. The echocardiographic findings of volume-overload heart failure  and LVAD recovery correlated well with the animal's clinical picture and hemodynamics, so we also scheduled LVAD implantation and support times according to these echocardiographic results. The changes in dystrophin expression in our pilot study were consistent with the development of heart failure and subsequent recovery after LVAD placement in humans . BecauseOne of our study's limitations was the lack of plasma profiles of dystrophin levels, which may be used as a predictive/clinical biomarker for left ventricular remodeling related to LVAD use. Such plasma profiles will be a main focus of our future studies involving a larger number of animals. Moreover, the location of the outflow-graft anastomosis may be considered another study limitation, as it may not be the anastomotic site currently preferred for most fully implantable LVAD outflow grafts.In this pilot experimental study, we have demonstrated an experimental animal model in which we created CHF in 2 adult sheep and subsequently reversed this condition by implanting 2 different centrifugal LVADs . The degree of remodeling was indicated by the disruption of dystrophin expression, as well as hemodynamic, echocardiographic, histologic, molecular, and clinical signs of heart failure. The reversal of heart failure , by means of mechanical circulatory assistance, was indicated by the normalization of dystrophin expression and integrity. We believe that this technique for creating and subsequently treating CHF with LVAD therapy may be useful in future studies investigating the diagnosis and prevention of CHF.


A comprehensive CMR exam was developed for evaluating right ventricle (RV) and pulmonary artery (PA), and was tested on 25 PA hypertension (PAH) patients. Standard non-CMR measurements were also collected. Comprehensive statistical analysis was conducted to study relationships between parameters, parameters’ significance, and data redundancy and reduction. The results showed strong correlations between most RV and PA parameters; and between most MRI parameters and gold standard PA pressure. In conclusion, RV and PA are coupled and affected in PAH. Both entities should be evaluated and interpreted together.Pulmonary artery (PA) hypertension (PAH) is characterized by elevated PA pressure (PAP), which increases right ventricular (RV) afterload. Although PAP is the gold standard for evaluating PAH, it is the RV condition that predicts patient survival. However, there is insufficient data about the relationship between RV and PA in PAH. The goal of this study is to investigate this relationship using CMR.Cine (RV cardiac index (CI), LV EF, ventricular vol index (VVI), ventricular mass index (VMI), right atrium (RA) size, MPA diameter, lunar index (LI) ); SENC ; Tricuspid Flow  filling); and PA Flow (pulse wave velocity (PWV), distensibility, accel-to-eject (a/e) time, flow rate, mean velocity). Mean PAP (mPAP), pulmonary vascular resistance (PVR), tricuspid jet velocity (Tri JV), 6 minute walk (6MW), and brain natriuretic peptide (BNP) results were obtained. Parameters were divided into 3 groups: RV ; PA ; and Measurements . Comprehensive statistical analysis included: Correlation (within- and across-groups); Regression ; and Principal Component Analysis (PCA) (data reduction). Multiple regression used backward deletion (mPAP is dependent variable).25 PAH patients, confirmed by cath, were scanned on 3T Siemens scanner. A comprehensive CMR exam was developed (~30 minutes) that included cine, strain-encoded (SENC), and flow (across main PA (MPA) and tricuspid valve) images. Image processing was conducted to obtain these parameters: strong correlations with ; moderate correlations with (CI); and weak correlations with . In regression analysis, the following parameters were eliminated in this order: RV group ; PA group ; both PA and RV groups for estimating mPAP . PCA analysis resulted in: RV group ; PA group ; Measurements .Fig.2 shows color-coded correlation map between all parameters, which shows different degrees of correlations. Correlation analysis results came in agreement with regression and PCA analyses. Strongly correlated within-group parameters reflected data redundancy. Weakly correlated parameters reflected parameters’ non-specificity. PA parameters showed RV and PA are coupled and their functions are affected in PAH. Both entities should be evaluated and interpreted together for more understanding of disease pathophysiology and better diagnosis and treatment.James & Esther King Grant # 09KN-03-23138.


Methods. 125 consecutive patients were prospectively enrolled in the study. Control group consisted of 78 asymptomatic age-matched healthy subjects who did not have any cardiovascular and respiratory diseases. All patients had undergone overnight polysomnography and standard transthoracic and tissue Doppler imaging echocardiogram. Results. The E/A ratio and the peak E wave at mitral flow were significantly lower and the peak A wave at mitral flow was significantly higher in OSA patients compared with control subjects. Left ventricle isovolumetric relaxation time (IVRT) and mitral valve flow propagation (MVFP) were significantly longer in OSA patients than in controls. Tissue Doppler derived S′ amplitude of lateral part at mitral valve (S′Lm) and E′ wave amplitudes both at the lateral (E′Lm) and septal parts of the mitral valve (E′Sm) were significantly lower in OSA patients compared to controls. Conclusion. Newly diagnosed OSA patients with normal global LV function have significantly impaired diastolic function and regional longitudinal systolic function. OSA is independently associated with these changes in LV function. The aim of the study was to evaluate whether obstructive sleep apnea (OSA) contributes directly to left ventricular (LV) diastolic and regional systolic dysfunction in newly diagnosed OSA with normal left ventricle ejection fraction.  Obstructive sleep apnoea (OSA) is a common condition affecting about 5–15% of adult population in developed countries. Prevalence is increasing with age, obesity, and chronic diseases . The maiManifested heart failure is the worst consequence of the left ventricular dysfunction caused by OSA. However, most of the patients with OSA without other cardiovascular disease usually exhibit normal LV ejection fraction (EF); nevertheless, they still may have clinical signs of LV systolic dysfunction. This is due to the fact that normal value of LVEF does not always mean normal LV systolic function. On the other hand, diastolic function is often impaired in OSA –9. MyocaMitral annular velocity evaluated by tissue Doppler imaging (TDI) is a sensitive marker of the LV longitudinal dysfunction. We assumed that early left ventricular systolic and diastolic dysfunctions are present in patients with newly diagnosed OSA, even when left ventricle ejection fraction is normal. Thus, the aim of the study was to evaluate whether obstructive sleep apnea (OSA) contributes directly to left ventricular (LV) diastolic and regional systolic dysfunction in newly diagnosed OSA with normal left ventricle ejection fraction.μmol/L), including chronic hemodialysispatients who did not have OSA ). All patients had complained of daytime sleepiness and/or loud snoring. The investigation was done to the principles enumerated in the Helsinki Declaration of 1975 and informed consent was obtained after full explanation of the procedure. Finally, 125 patients  were enrolled in the study.A total of 792 consecutive patients who had undergone overnight polysomnography (PSG), with newly diagnosed OSA at the Center for Sleep Medicine, Bezanijska kosa, from January 2011 to January 2013, were enrolled in the study. Among them, the patients who met the following conditions that might have had an influence on the results of echocardiographic parameters were excluded: (1) central sleep apnoea, (2) history of coronary artery disease or electrocardiographic changes suggestive of myocardial infarction, (3) proved myocardial ischaemia at the ergometry testing, (4) global LV systolic dysfunction (LVEF < 50%) or a history of congestive heart failure, (5) diabetes mellitus, (6) moderate to severe valvular heart diseases, (7) hypertrophic cardiomyopathy, (8) history of chronic obstructive pulmonary disease or asthma, (9) atrial fibrillation, (10) previous diagnosis of OSA and/or the previous use of continuous positive airway pressure therapy, and (11) chronic renal impairment  was recorded continuously with a pulse oximeter. Apnea was defined as the disappearance of airflow for over 10 s; hypopnea was defined as a 50% or greater decrease in airflow lasting for more than 10 s associated with arousal or a 3% or greater decrease in arterial oxygen saturation from the baseline level. The AHI was calculated as the total number of apnea and hypopnea episodes per hour of sleep. According to the AHI, the patient was classified as having OSA when the obstructive component was over 5 events per hour. Severe OSA was classifies as AHI > 30 events/h [Overnight fully attended PSG monitoring was performed with the Alice 4 Sleep System  in the referral Center for Sleep Medicine using standard recording techniques and precise protocol of PSG monitoring . Surfaceevents/h .Echocardiography was performed in the left lateral decubitus position with a commercially available ultrasound machine  and 3S-RS (3.5 MHz) probe. All images were obtained from standard parasternal and apical position using 2D, M-mode, and Doppler echocardiographic techniques. All examinations were performed by an experienced cardiologist who was blind for the results of polysomnography. The LV end-diastolic and end-systolic dimensions, as well as interventricular septum and posterior wall thicknesses, were obtained from M-mode echocardiography . LVEF waE), late diastolic peak flow velocity (A), E/A ratio, and deceleration time of the E wave velocity were measured and then calculated from three consecutive cardiac cycles [Pulse Doppler sample volume was placed at the mitral valve tips in the apical four-chamber view to record LV inflow velocity. From LV inflow velocity, early diastolic peak flow velocity (c cycles . Isovoluc cycles .S′), peak early (E′), and late (A′) diastolic mitral septum and lateral annular velocities were measured [Tissue Doppler echocardiography was recorded from the apical four-chamber view with the pulse-wave Doppler sample volume placed on the septal and lateral corners of the mitral annulus. Care was taken to ensure an ultrasound beam parallel to the direction of the mitral annular motion. Filters were set to exclude high-frequency signals, and gains were set to obtain clear tissue signals with minimal background noise. Peak systolic . A Clinical characteristics of OSA patients and control subjects are shown in The results of polysomnography are described in Standard 2D echocardiographic measurements, left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic dimension (LVESD) were significantly larger in patients with OSA compared to control subjects, as well as interventricular septum thickness (IVS) and posterior wall thickness (PW). There were significant differences in right ventricle dimension (RV) and right ventricular fractional area change (FAC RV). However, parameters of global left ventricular systolic function, global ejection fraction (EF), and fraction of shortening (FS) were similar in both groups .E/A ratio and the peak E wave at mitral flow were lower and the peak A wave at mitral flow was higher in OSA patients compared with control subjects. IVRT and MVFP were significantly longer in OSA patients compared to the controls. Tissue Doppler derived S′ amplitude of lateral part at mitral valve (S′Lm) and E′ wave amplitudes both at the lateral (E′Lm) and septal part of the mitral valve (E′Sm) were significantly lower in OSA patients compared to controls. However, although the amplitude of the S′ of the mitral part of the mitral valve (S′Sm) was also lower in OSA patients compared to controls, the difference was not significant   .The data in our cross-sectional study indicate impaired LV diastolic relaxation as well as impaired LV longitudinal systolic function in patients with newly diagnosed OSA and normal left ventricle ejection fraction. Several previous studies have shown that OSA is frequently accompanied with diastolic dysfunction –7. HowevThe present study demonstrated that OSA in newly diagnosed patients independently affected both LV regional systolic and diastolic functions. Controversy exists regarding LV global and regional systolic function in OSA. According to the previous data, there is a higher proportion of heart failure in patients with OSA compared to general population. However, most of them have normal ejection fraction despite signs of the heart failure , 21. PreImpairment of the longitudinal left ventricle function despite normal LV ejection fraction in patients with newly diagnosed OSA has serious implications: longitudinal fibers, which are subendocardially located, are more susceptible to myocardial ischemia caused by the apnea-hypopnea episodes of the OSA. Normal ejection fraction is due to compensatory unchanged normal radial LV function. An increased LV wall tension and preload caused by the OSA lead to LV longitudinal systolic dysfunction and increased myocardial wall thickness is the consequence of the compensatory mechanism aiming at decreasing LV wall tension and protecting myocardial function.As the LV hypertrophy and concentric remodeling progress, the subendocardial myocardial layer responsible for the longitudinal shortening becomes more susceptible to ischemic apoptosis and fibrous phenomena, resulting in reduced LV longitudinal shortening in the early stages of the OSA. Depressed myocardial contractile reserve in patients with obstructive sleep apnea was also proven by dobutamine stress echocardiography, supporting this pathophysiological rationale . SeveralThe study has some limitations. Although patients and control subjects were age matched, significant differences of prevalence of coronary risk factors and body mass index between the two groups may have an impact on the left ventricular dysfunction. Thus, the early screening for coronary artery disease in OSA patients should be mandatory. Second, although OSA patients had severe degree of the disease, the real duration of the process could not be precisely determined.However, the strength of the present study is twofold. First, this is the first echocardiographic study in OSA patients in Serbian population and in the same time one of the largest echocardiographic studies in OSA patients in general. Second, adjustments of echocardiographic parameters to BMI and hypertension have been successfully done.The study revealed that a greatest proportion of patients with newly diagnosed OSA has severe grade of OSA.In newly diagnosed patients with OSA with normal left ventricle ejection fraction, left ventricular function is severely impaired, both diastolic and systolic.There is a strong correlation between OSA and impaired left ventricle diastolic and regional systolic function, even after adjustments to hypertension and BMI, identifying OSA as an independent risk factor for early left ventricular diastolic and systolic dysfunction.


Staged palliation culminating with the Fontan procedure has dramatically increased survival in children with single ventricle anatomy. However, long-term morbidity and mortality continue to be significant. This has been linked to ventricular myocardial fibrosis and scarring and subsequent altered contractile mechanics with abnormal regional wall motion and strain, but has not been fully elucidated. In this study, we sought to more precisely characterize these structural changes via magnetic resonance imaging and quantitatively assess ventricular mechanics through the measurement and calculation of MRI-derived displacement fields and regional wall strain to discern any association between fibrosis and function in the post-Fontan population.The study population consisted of patients with single systemic ventricle anatomy of left ventricular morphology. Inclusion criteria included age > 5 years, Fontan completion > 2 years from time of MR study, and ability to undergo MRI without sedation. Studies on 22 Fontan subjects and 39 normal control subjects were completed. The MR protocol included cine bright-blood sequences for function, SPAMM cine gradient-recalled echo sequences for tagged analysis, and delayed contrast enhancement with gadolinium for tissue characterization. The tagged images were used to calculate a 3-dimensional LV myocardial displacement field via a validated methodology incorporating interpolation of tag line and surface deformation and finite element approximation. Strain values throughout the myocardium were then calculated from this continuous displacement field. Delayed myocardial enhancement was evaluated using standard techniques to identify regions of fibrosis. All strain values were expressed as means with standard deviations, and two-way ANOVA was utilized to compare strain in normal and fibrotic regions.In the Fontan cohort analyzed thus far, three distinct myocardial fibrosis/scarring patterns have been identified in about half the subjects - localized subendocardial, transmural, and diffuse. In these areas, altered contractile mechanics were present with decreased regional and global strain. Compared to normal subjects, in whom no fibrosis or scarring was demonstrated, circumferential and longitudinal strains were significantly (p < 0.05) decreased - circumferential: -0.18 +/- 0.07 (Fontan) vs. -0.26 +/- 0.04 , longitudinal: -0.13 +/- 0.06 (Fontan) vs. -0.21 +/- 0.04 . Furthermore, median systemic ventricular ejection fraction was also decreased in the Fontan cohort versus the normal cohort - 42% vs. 65%.In the post-Fontan population, fibrotic LV myocardial segments demonstrate decreased thickening and abnormal wall motion with decreased regional strain measures and global ventricular EF. Cardiac MR techniques are a valuable tool to assess myocardial characteristics and contractile mechanics in these patients.No current funding.


Pathophysiology of heart failure has been considered to be a damaged state of systolic function of the heart followed by a state of low cardiac output that is, systolic heart failure. Even if systolic function is preserved, left ventricular filling in diastole can be impeded and resulted in elevation of filling pressure and symptoms of heart failure. This kind of heart failure is called diastolic heart failure. Nowadays, diastolic heart failure is referred to as heart failure with preserved ejection fraction (HFpEF), whereas systolic heart failure is referred to as heart failure with reduced ejection fraction (HFrEF). In this paper, the similarities and differences between the pathogenesis and pathophysiology of diastolic and systolic heart failure were reviewed. Although diastolic heart failure is a common condition of heart failure worldwide, its pathophysiology has not been sufficiently elucidated. This is thought to be the most significant reason for a lack of established treatment methods for diastolic heart failure. We hope to proceed with future studies on this topic. Pathophysiology of heart failure has been considered to be a damaged state of systolic function of the heart followed by a state of low cardiac output (systolic heart failure). However, even if systolic function is preserved, left ventricular filling in diastole is impeded due to various factors. This condition leads to congestive heart failure due to the rise in left ventricular end-diastolic pressure and the decrease in cardiac output. This kind of pathophysiology is now known as diastolic heart failure , 2. In rDiastole of the left ventricle is composed of isovolumic relaxation and ventricular filling. Relaxation of the left ventricle is an active process that occurs as a result of energy-dependent uptake of intracellular calcium by the sarcoplasmic reticulum, whose concentration has risen during the systolic phase.Relaxation of the left ventricle is impaired in a disease state caused by energy metabolism disorders or calcium-handling abnormalities such as myocardial ischemia and myocardial hypertrophy. Left ventricular filling phase abnormality, namely, elevation of left ventricular stiffness, influences left ventricular flow dynamics during filling phase and is commonly caused by myocardial fibrosis or hypertrophy.When left ventricular diastolic function is impaired, cardiac output is reduced because the left ventricle is not filled enough in diastole due to left ventricular inflow obstruction. By contrast, to compensate for reduced cardiac output, increasing the inflow pressure to the left ventricle (and consequently left ventricular end-diastolic pressure) becomes necessary, which in turn increases left atrial pressure. As a result, left ventricular dysfunction easily and directly causes pulmonary congestion.Emax (absolute index of contractibility). Therefore, pulmonary congestion is induced as a result of the significant increase in left ventricular end-diastolic pressure  when conditions (1) and (2) are met . When diAccording to reports by Owan et al. and Bhatia et al., roughly half of hospitalizations for heart failure are due to diastolic heart failure , 13. ComThe main differences between diastolic and systolic heart failure are the presence of contractile dysfunction and left ventricular remodeling . In systIn recent years, several reports on important association of various biomarkers for heart failure and subtypes of heart failure have been published –19. AccoThe histological features of systolic heart failure include myocardial hypertrophy, loss of myocardial cells, and restructuring of the extracellular matrix. Meanwhile, significant myocardial fibrosis together with myocardial hypertrophy is typical in diastolic heart failure. Myocardial fibrosis is thought to be the main factor in increased stiffness .β via macrophage infiltration and activation mediated by monocyte chemotactic protein-1. The resulting perivascular inflammation is reported to be the cause of reactive fibrosis of myocardium [Mechanical stimulation to the myocardium is the main factor of myocardial hypertrophy, while myocardial fibrosis may be caused by humoral factors such as various cytokines, growth factors, and hormones. In hypertensive HFpEF model rats, oxidative stress was increased and angiotensin II was produced within the arterial walls due to high blood pressure. This resulted in fibroblast activation and increased production of transforming growth factor-ocardium –16. In Docardium .In addition to the quantitative increase in collagen and distribution abnormalities, qualitative changes are also involved in increased myocardial stiffness caused by fibrosis. In Dahl salt-sensitive rat HFpEF models, the increase in the ratio of stiff type I collagen to type III collagen, which is highly distensible, and increased collagen cross-linking are reported to important factors of increased myocardial stiffness .In diastolic heart failure, myocardial stiffness of cardiomyocytes per se also increases. Detailed mechanism for this remains unclear but is thought to be due to changes in structural proteins associated with myocardial hypertrophy. Titin, which is a giant sarcomeric protein, acts as a molecular spring and plays a large part in the distensibility of cardiomyocytes during diastole. However, in diastolic heart failure, compared with systolic heart failure, the ratio of large, distensible N2A isoforms small, rigid N2B isoforms to was found to decrease .To date, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARB), beta-blockers, and statins have been tried for HFpEF. Although they are authorized for optimal treatment for HFrEF, none of them can provide the optimal treatment for HFpEF . ACEI peA neutral outcome in HFpEF compared with a positive outcome in HFrEF, as occurred with ACEIs, ARBs, and beta-blockers, might be compatible with flawed study design. However, a positive outcome in HFpEF compared with a neutral outcome in HFrEF, as occurred with statins, can no longer be attributable to study design but supports different signal transductions driving myocardial remodeling in HFpEF and HFrEF .Several compounds seem to be promising for drug target of HFpEF. Phosphodiesterase 5 inhibitors (PDE5I) increase cGMP level, attenuate adrenergic stimulation, reduce ventricular-arterial stiffening, antagonize maladaptive chamber remodeling, improve endothelial function, and reduce pulmonary vascular resistance –30. The Despite the fact that diastolic heart failure is a common condition of heart failure, its precise definition still remains unclear. Therefore, the similarities and differences between the pathogenesis and pathophysiology of diastolic and systolic heart failure have not been sufficiently elucidated. This is thought to be the most significant reason for a lack of established treatment methods for diastolic heart failure. We hope to proceed with future studies on this paper.


QT), a presumptive novel parameter for arrhythmia prediction, in professional soccer players.Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization  and age-matched healthy volunteers who do not participate in competitive sports . The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals.QT was significantly higher in players both at rest and immediately after the game compared to controls .Heart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest . QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STVQT is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population.STV Sports activities are undoubtedly beneficial that improve quality of life and life expectancy, however, a number of tragic athletic field deaths have been reported in recent years, attracting widespread media attention. A significant amount of these cases involved elite professional soccer players Physical conditioning in competitive athletes induces cardiovascular adaptation including lower resting heart rate  and increased cardiac mass (hypertrophy) and volume as a consequence of increased demand on the cardiovascular system, called “athlete's heart”, a physiological compensatory mechanism that reverses in most cases following the termination of sports activities Ks, IKr and IK1) in the chronic AV block dog model has been associated with increased incidence of serious ventricular arrhythmias probably due to decreased repolarization reserve Myocardial hypertrophy in pathological settings in humans Furthermore, the duration of repolarization is cycle length dependent and low heart rate in athletes leads to prolonged repolarization. These changes can also be associated with increased propensity for ventricular arrhythmias, including Torsades de Pointes (TdP). It is conceivable that prolonged repolarization, increased spatial dispersion of repolarization and a possibly impaired repolarization reserve due to myocardial hypertrophy-induced downregulation of potassium currents might represent increased risk for the development of ventricular arrhythmias, including TdP that can degenerate into VF and lead to sudden cardiac death in athletes.In theory, if athletes with no apparent structural cardiac abnormalities but with increased susceptibility for cardiac arrhythmias could be identified, current screening methods could be improved to further decrease the incidence of sudden cardiac death in young athletes. However, current techniques for the reliable prediction of TdP and other, potentially fatal ventricular arrhythmias remain unsatisfactory. Based on recent evidence, in addition to the prolonged QTc interval, the short-term variability (STV) of repolarization can probably more reliably predict the development of TdP both in humans QT) has been associated with latent repolarization disorders and increased suspectibility to serious ventricular arrhythmias in LQT patients and patients with dilated cardiomyopathy Since elevated STV of the QT interval (STVThe studies described here were carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and were approved by the Scientific and Research Ethical Committee of the Medical Scientific Board at the Hungarian Ministry of Health (ETT-TUKEB), under ethical approval No. 4987-0/2010-1018EKU (338/PI/010). All subjects have given written informed consent of the study.2), and 76 male, age-matched healthy control sedentary subjects who did not participate in sports activities . Professional soccer players or age-matched controls were excluded from the study if they exhibited an excessive number (>5%) of ectopic atrial or ventricular beats, were in a rhythm other than normal sinus rhythm, had repolarization abnormalities , had a permanent pacemaker or had any other disorder such as serious retinopathy, symptomatic cardiac and/or pulmonary disease, acute metabolic disease, had excessive noise on the electrocardiographic signal that precluded analysis of the ECG waveform, were on any medication likely to affect the investigated parameters or consumed significant amount of food within 3 hours or drank alcohol, coffee or smoked within 10 hours. All of the control individuals and soccer players were of European descent.The study population consisted of 76 male professional soccer players from the Hungarian Premier League , Framingham (QTc = QT+[0.154 * {1000-RR}]) and the Hodges formulas (QTc = QT+1.75 * [{60 000/RR}−60]).Five-minute 12-lead electrocardiograms (lead II) were recorded from professional soccer players and age-matched healthy human volunteers using Cardiosys H-01 software  in the supine position. The ECGs were digitized and stored on a computer for later analysis. The RR, QT intervals were measured using automated algorithms as the average of 30 beats, the frequency corrected QT interval (QTc) was calculated using Bazett's (QTc = QT/√RR), Fridericia  and also approximately 20 minutes after the end of the game in the dressing room.The calculation of the short-term beat-to-beat variability of repolarization was chosen since it is a relatively simple method that has been suggested as a future screening tool; moreover it has been shown in animal studies n+1−Dn| (30×√2)−1, where D is the duration of the RR or QT intervals. This calculation defines the STV as the mean distance of points perpendicular to the line of identity in the Poincaré plot.Using 30 consecutive beats, RR and QT intervals were plotted against their respective previous interval and Poincaré plots were constructed as described previously Echocardiographic measurements were performed at rest on 23 professional soccer players and 23 age-matched controls using a Dornier AI 4800 (Germany) echocardiograph with a 2.5 MHz transducer. Two-dimensionally guided M-mode recordings were obtained parasternally in accordance with the recommendations of the American Society of Echocardiography t-test. ECG parameters of athletes before and after the game were compared by one-way analysis of variance (ANOVA) followed by a paired t-test. A p value of <0.05 was considered significantly different. Statistical analyses were performed using Statistica for Windows (version 9).Body weight, BMI, age and ECG interval data are expressed as means ± standard error of the mean (S.E.M.). Comparisons between controls and soccer players were made using the unpaired Student's Professional soccer players exhibited significantly higher values in interventricular septum, left ventricular posterior wall thickness and in left ventricular internal diameter during diastole compared to age-matched controls . These rThe development of athlete's heart in response to long-term physical conditioning is characterized by increased vagal tone. As expected, the RR intervals in soccer players were significantly longer before the game compared to age-matched volunteers . ConsequThe duration of cardiac repolarization is cycle length dependent where slower heart rates lead to prolonged repolarization. Accordingly, significantly longer QT intervals and were measured in soccer players before the game . HoweverIn order to reliably assess the duration of ventricular repolarization and to minimize the influence of changing heart rate on the QT interval, it is necessary to carry out frequency correction of the QT interval. However, recent work has shown that Bazett and Fridericia correction formulas described over 90 years ago QT can be, at least in part, influenced by the short-term variability of the RR interval, the STVRR was also calculated in both groups. Soccer players before the competitive game exhibited a significantly larger STVRR compared to controls, however, this difference disappeared after the game, when their heart rates were similar to controls  and grouped average data show, the short-term beat-to-beat variability of the QT interval was significantly higher in soccer players compared to controls . Importae values . Histogrcontrols  and 6A. controls , the disthe game . These rQT was markedly larger than the average STVQT in the soccer player group  STVQT on repeated measurement was due to the well-known de-training phenomenon in an athlete who had been out of training due to injury was unclear.In six players before the game the STVQT was accompanied by a prolonged QT, and a lengthened Fridericia and Hodges QTc interval in these athletes.The main and novel finding of this study is that short-term beat-to-beat variability of the QT interval is significantly increased in professional soccer players compared to age-matched healthy volunteers. The increased STVIn competitive athletes, the cardiovascular system adapts to chronic physical exercise by the development of “athlete's heart”, characterized by lower resting heart rate , increased ventricular mass (hypertrophy) and volume to meet the increased demand.Ks), develops Ks has been identified as a key component in the somewhat redundant repolarizing capacity of the myocardium, termed repolarization reserve K1, Ito, IKr and IKs has also been shown both in animal models and patients with heart failure, leading to prolonged repolarization, increased dispersion of repolarization with concomitant increase in the incidence of serious ventricular arrhythmias In a reasonable animal experimental analogue for athlete's heart, in dogs with chronic AV block, myocardial hypertrophy and downregulation of potassium channels, most notably of the slow component of the delayed rectifier potassium current (If) current There are two main prerequisites for the development of TdP chaotic ventricular tachycardia and consequent fatal ventricular fibrillation: an arrhythmia substrate  and a trigger (extrasystole in the vulnerable period) for the initiation of the arrhythmic event. Increased vagal tone in athletes lowers heart rate that favors prolonged repolarization and increased inhomogeneity. The possible potassium channel downregulation due to myocardial hypertrophy also prolongs repolarization and reduces repolarization reserve. In some athletes, loss of function mutations of repolarizing potassium channels and/or gain of function mutations of sodium channels may be present. In these individuals with impaired repolarization reserve, additional, most likely moderate potassium channel blocking effects can provoke TdP arrhythmias that, in some cases lead to ventricular fibrillation. Theoretically, in this scenario a number of conditions, compounds and dietary constituents can precipitate such events of sudden cardiac death (as recently reviewed by Varró and Baczkó) in vivo animal experiments using species that are electrophysiologically relevant for humans in regard of ventricular repolarization in vitro studies QT correlated with elevated incidence of lethal ventricular arrhythmias and sudden cardiac death. Importantly, the patients and experimental animals in all of these studies had narrowed repolarization reserve, albeit due to different mechanisms, ranging from pharmacological inhibition of repolarizing potassium channels to downregulation of potassium currents during electrical remodeling and including mutations in ion channels leading to congenital long QT syndromes. Therefore, based on these studies and the present results, the elevated temporal beat-to-beat variability in competitive soccer players may indicate a larger repolarization instability and an increased propensity for ventricular arrhythmias. Notably, physical deconditioning in trained athletes with no cardiac structural abnormalities decreased the incidence and complexity of ventricular tachyarrhytmias The reliable identification of patients at risk for serious ventricular arrhythmia and sudden cardiac death remains elusive. Accumulating evidence suggests that QT interval prolongation alone cannot reliably predict the development of TdP since cardiac repolarization reserve may be reduced without siginificant changes in the duration of cardiac repolarization. A number of clinical studies For purely practical and logistic reasons echocardiographic assessment of all soccer players and all controls were not performed in this study. However, our echocardiography data randomly performed on 23 soccer players and 23 controls support the findings of a number of previous studies showing that endurance athletes, including soccer players, as part of the cardiovascular system's physiological response to long-term intense physical training, develop athlete's heart that features myocardial hypertrophy RR on STVQT cannot be ruled out, however, in professional soccer players STVRR was reduced and was similar to control values after the competitive game while STVQT remained significantly higher, strongly suggesting that STVQT was increased irrespective of changes in STVRR. The short-term variability of the monophasic action potential was found to be partially influenced by pacing cycle length and was moderately decreased at faster cycle lengths in anesthetized dogs with chronic AV block characterized by marked bradycardia and myocardial hypertrophy Since the duration of repolarization is cycle length dependent, variability in the RR interval could influence QT variability. Based on our results, the influence of STVQT in the present study in soccer players, who were chosen as subjects of the study since the different degrees of cardiac hypertrophy found in athletes of different sports QT can be different in other sports, depending on type, intensity and duration of various training schedules used in different sports. Further studies are needed to confirm whether STVQT elevation is uniformly present in other endurance athletes.We found elevated STVQT may be more predictive for the development of serious ventricular arrhythmias than conventional ECG parameters, such as the prolongation of the QTc interval. In our study, some soccer players exhibited greatly increased STVQT even when compared to other players, suggesting that it may be beneficial to screen athletes for elevated repolarization instability by adding the relatively low cost STVQT determination to routine ECG examinations. Individual athletes with large STVQT could be then subjected to more detailed and sophisticated examinations  to carefully evaluate their vulnerability to ventricular arrhythmias and sudden cardiac death. Importantly, our results further support the inclusion of ECG in preparticipation athlete screening expertly worked out by Corrado et al.QT could also be added to the ECG evaluation in case our findings can be confirmed in a broader athlete population. It is important to emphasize that no arrhythmias were observed among soccer players in this study and further, more comprehensive investigations are needed to establish whether the higher STVQT relates to higher arrhythmia propensity in this population. This study also warrants the investigation of STVQT in top athletes with various training levels and in a larger number of athletes preferably taking part in different types of sports activities to enable investigators to make a direct link between STVQT, arrhythmia susceptibility and sudden cardiac death in top competitive athletes.In conclusion, the short-term variability of the QT interval is elevated in professional soccer players, which, according to our present knowledge, might indicate increased repolarization instability even without any underlying cardiac disease. Based on the available literature, decreased repolarization reserve due to downregulation of certain repolarizing potassium currents associated with myocardial hypertrophy may underlie these changes. As clinical and animal studies illustrate, increased STV


First pass perfusion CMR is a well-validated technique for the detection of inducible myocardial ischaemia. However, limited data are available on the feasibility of first pass perfusion CMR and quantitative deconvolution analysis in the context of reduced LV function.The aim of this study was to assess effects of reduced LV function and LV dilatation on the characteristics of signal in the left ventricle  and in the myocardium (MSI), and to test the feasibility of quantitative perfusion analysis with Fermi deconvolution in this cohort of patients.We retrospectively identified fifteen consecutive patients who had undergone perfusion CMR in the presence of impaired LV function (left ventricular ejection fraction (LVEF) <50%) at our centre. Five healthy volunteers were enrolled in the study as control subjects. Perfusion data were obtained using a pre-bolus technique and 0.075 mmol/kg Gadobutrol  injected at 4ml/minute followed by a 20 ml saline flush. Images were acquired on a Philips Achieva 3T (TX) system, equipped with a 32-channel cardiac phased array receiver coil . First-pass perfusion images were acquired using a saturation recovery gradient echo method .The following parameters were evaluated from stress perfusion series in order to assess the quality of the data and assess the effect of abnormal cardiac structure and function: time to peak, peak value and maximum slope of the AIF and of the MSI. Quantitative analysis was performed by Fermi deconvolution.Detailed results are reported in Table. The left ventricular (LV) systolic function was lower, with higher end-diastolic (LV EDV) and end-systolic volumes (LV ESV) in the patient compared with the normal group.Both the AIF and the MSI were reduced in peak amplitude, maximum upslope and time to peak in patients compared with controls. However, the ratio between the peak of AIF and MSI and the time to peak of the AIF and MSI was constant between patients and controls, suggesting the feasibility of deconvolution quantitative analysis on both groups.Fermi deconvolution showed a trend towards an overall lower perfusion rate in normal segments in the patients group (2.2±1.2 ml/g/min) compared with controls  however non-significant. Reduced perfusion rate was found in visually abnormal segments in patients .Our results show that reduced cardiac function modulates the characteristics of both the AIF and MSI. However, the relationship between AIF and MSI remains unaffected. Fermi deconvolution analysis appears applicable to both groups, supporting the feasibility of first pass perfusion CMR as a clinical tool in patients with reduced LV function.None.


Myocardial tissue characterization using T2* relaxation mapping techniques is an emerging application of clinical cardiovascular magnetic resonance imaging. The increase in microscopic susceptibility at higher magnetic field strengths renders myocardial T2* mapping at ultrahigh magnetic fields conceptually appealing. This work demonstrates the feasibility of myocardial T2* imaging at 7.0 T and examines the applicability of temporally-resolved and high spatial resolution myocardial T2* mapping.Imaging was conducted using a 7.0 T whole body MR scanner  together with a 16 channel TX/RX coil array on 8 healthy subjects without any known history of cardiac disease. 9 CINE datasets were acquired with echo times ranging from 2.04ms to 10.20ms with a interleaved multi-shot multi-echo gradient echo technique over three breath holds. Other imaging parameters were set to: flip angle=20°, acquisition data matrix=256x224, FOV=(288x252)mm2, in-plane resolution=(1.1x1.1)mm2, slice thickness=4mm and acceleration using GRAPPA (R=3). Prior to T2* mapping, volume selective B0 shimming was conducted to reduce static magnetic field inhomogeneities.After volume selective shimming, a mean peak-to-peak B0 difference of approximately 80 Hz was found across the entire heart for a four chamber view and a mid-ventricular short axis view of the heart Fig. The thrNo severe susceptibility artifacts were detected in the septum and in the lateral wall for T2* weighting. For TE>7ms, a signal void (related to susceptibility weighting) was observed within the anterior and inferior myocardial segments. The longest T2* values were found for anterior (T2*=14.0 ms), anteroseptal (T2*=17.2 ms) and inferoseptal (T2*=16.5 ms) myocardial segments. Shorter T2* values were observed for inferior (T2*=10.6 ms) and inferolateral (T2*=11.4 ms) segments. A significant difference (p=0.002) in T2* values was observed between end-diastole and end-systole as illustrated in Figure Our results underscore the challenges of myocardial T2* mapping at 7.0 T due to the propensity to macroscopic susceptibility artefacts and T2* shortening, but demonstrate that these issues can be offset by using tailored shimming techniques together with dedicated acquisition schemes.


Way and the importance of the assessment of left ventricular contractile reserve in patients with dilated cardiomyopathy, as well as differences between patients with and without preserved left ventricular contractile reserve, the current problems that are being intensively studied.We studied 55 consecutive patients with dilated cardiomyopathy  male). All patients underwent exercise stress-echocardiography on tredmil using modified Bruce protocol. Contractile reserve was assessed by measuring changes in wall motion score index (ΔWMSI) at rest and at peak exercise.Preserved contractile reserve had 19 patients (34.5%). Patients with and without preserved left ventricular contractile reserve were no different in age, gender, disease duration, NYHA class, presence of atrial fibrillation and left bundle branch block. Patients with preserved contractile reserve had a smaller end-diastolic  and end-systolic left ventricular dimension , lower left ventricular mass index , a higher slope Vp measured by color M-mode , higher systolic mitral annular displacement measured by tissue Doppler , smaller end-diastolic  and end-systolic left ventricular volume index , higher left ventricular ejection fraction  and lower wall motion score index .Patients with preserved left ventricular contractile reserve were morphologically and functionally less damaged left ventricle.