Diastolic dysfunction is a sensitive early indicator of heart failure and can provide additional data to conventional measures of systolic function. Transmitral Doppler ultrasound, which measures the one‐dimensional flow of blood through the mitral valve, is currently the preferred method for the measurement of diastolic function, but the measurement of the left ventricular volume changes using high‐temporal‐resolution cinematic magnetic resonance imaging (CINE MRI) is an alternative approach which is emerging as a potentially more robust and user‐independent technique. Here, we investigated the performance of high‐temporal‐resolution CINE MRI and compared it with ultrasound for the detection of diastolic dysfunction in a mouse model of myocardial infarction. An in‐house, high‐temporal‐resolution, retrospectively gated CINE sequence was developed with a temporal resolution of 1 ms. Diastolic function in mice was assessed using a custom‐made, open‐source reconstruction package. Early (E) and late (A) left ventricular filling phases were easily identifiable, and these measurements were compared directly with high‐frequency, pulsed‐wave, Doppler ultrasound measurements of mitral valve inflow. A repeatability study established that high‐temporal‐resolution CINE MRI and Doppler ultrasound showed comparable accuracy when measuring E/A in normal control mice. However, when applied in a mouse model of myocardial infarction, high‐temporal‐resolution CINE MRI indicated diastolic heart failure (E/A = 0.94 ± 0.11), whereas ultrasound falsely detected normal cardiac function (E/A = 1.21 ± 0.11). The addition of high‐temporal‐resolution CINE MRI to preclinical imaging studies enhances the library of sequences available to cardiac researchers and potentially identifies diastolic heart failure early in disease progression. Aatrial/late‐filling phaseCINEcinematicCVcoefficient of variationEearly‐filling phaseECGelectrocardiographyEDVend diastolic volumeEFejection fractionESVend systolic volumeFAflip angleFLASHfast low‐angle shotFOVfield of viewGd‐DTPAgadolinium‐diethylenetriaminepentacetateHFpEFheart failure preserved ejection fractionHTRhigh temporal resolutionIRinversion recoveryLADleft anterior descending coronary arteryLGElate gadolinium enhancedLVleft ventricular/left ventricleMRImagnetic resonance imagingNFnumber of framesNRnumber of sequence repetitionsRCrepeatability coefficientRFradiofrequencySEMstandard error of the meanSVstroke volume1In the clinical setting, cardiac function is most commonly assessed using measures of contractile, systolic function, such as ejection fraction (EF), where a reduced EF <50%) is a primary indicator of global systolic dysfunction.0% is a pPulsed‐wave Doppler ultrasound imaging is the current standard for the diagnosis of diastolic dysfunction in patients,When using ultrasound, diastolic function is quantified by the measurement of blood velocity across the mitral valve, whereas, with MRI, quantification is based on the derivative of time–volume curves of the left ventricle (LV) blood pool chamber. With both modalities, the characteristic early‐filling (E) and atrial‐filling (A) phases can be identified. The ratio (E/A) of these two peaks is the metric most frequently used to diagnose diastolic dysfunction.In rodents, ultrasound remains the standard measure of diastolic dysfunction, but is also limited by user‐dependent transducer positioning, a small acoustic window, one‐dimensional acquisition and high heart rates, which can lead to merging of the E and A phases.To date, however, HTR‐CINE techniques have not been compared with the ultrasound assessment of diastolic function. This comparison is important because the two modalities adopt intrinsically different approaches to the quantification of E/A: Doppler ultrasound measures transmitral blood flow directly, whereas HTR‐CINE methods measure local changes in LV volume.n = 8). Following optimisation of the MRI protocol, both modalities were then applied to the measurement of diastolic function in mice after surgically induced myocardial infarction (n = 13).Therefore, in this study, we directly compared a retrospectively gated HTR‐CINE sequence with ultrasound to validate the MRI approach, determine the repeatability of both techniques and examine how both methods perform when applied to a mouse model of heart failure. A single‐slice, retrospectively‐gated, HTR‐CINE sequence with an effective frame rate of 90 frames per cardiac cycle was used to measure diastolic function based on volumetric alterations in the LV, and compared with one‐dimensional, pulsed‐wave, Doppler ultrasound measures of mitral filling velocities. The variability and repeatability of both ultrasound and HTR‐CINE MRI were compared by repeat measurements of E/A ratios in normal control mice  Act 1986 .2.2Mice were anaesthetised in 4% isoflurane, intubated and maintained at 1.5% isoflurane in oxygen. Analgesia (0.1 mg/kg intramuscular buprenorphine) was administered before and 6 and 24 h after surgery. Body temperature was monitored using a rectal thermometer and maintained using a heated operating table. Open‐chest surgery was performed to gain access to the heart. The left anterior descending coronary artery (LAD) was permanently occluded using a 5–0 prolene suture approximately 2 mm below the origin. All surgical openings were closed and the animal was recovered.2.3MRI measurements were performed on a 9.4‐T horizontal bore scanner  with a 115/60/HD 1000‐mT/m gradient insert and a 35‐mm‐volume radiofrequency (RF) coil . Mice were anaesthetised with 1.5–2.0% isoflurane in 2 L/min oxygen and positioned supine in a cradle for imaging. Body temperature was regulated using a hot water system and monitored using a rectal probe. Respiration was monitored using a neonatal apnoea pad taped to the abdomen of the animal. Electrocardiography (ECG) was monitored using a subcutaneous three‐lead electrode configuration , which was robust to interference from the imaging gradients. Two of the electrodes were placed at the base of each fore leg and the final electrode was placed in the right flank of the mouse. For gadolinium‐based experiments, an intraperitoneal infusion line was inserted into the mouse.2.4Ultrasound measurements were performed on a Vevo 2100 system  using an MS550D 30‐MHz transducer . Mice were anaesthetised with 1.5–2.0% isoflurane in 2 L/min oxygen and positioned supine on a physiological monitoring platform which simultaneously regulated body temperature, whilst measuring respiration and ECG traces. Prior to imaging, hair was removed from the chest to reduce the attenuation of the ultrasound signal.2.5n = 6 mice were imaged with both modalities; two mice died under anaesthesia before the second trial of ultrasound. All eight mice were imaged with repeat measures of MRI. Each mouse in group one was imaged for a maximum total of 2.5 h.Two cohorts of 10–12‐week‐old male C57BL/6 mice were imaged using both ultrasound and HTR‐CINE MRI. In group one, control mice were imaged to study the repeatability of both modalities. First, mice were imaged with ultrasound, then taken for MRI with a standard prospective CINE sequence and an HTR‐CINE sequence. Animals were then removed and repositioned in the scanner before both MRI sequences were repeated. This was followed by a second trial of ultrasound. In total, n = 13 mice underwent surgically induced permanent occlusion myocardial infarction (as described above). Four weeks later, all animals were imaged with ultrasound, followed by standard CINE and HTR‐CINE imaging. Following these protocols, infarcted animals were injected with gadolinium contrast agent and imaged with an inversion recovery late‐gadolinium‐enhanced (IR LGE) sequence for infarct size quantification.In group two, 2.6The acquisition of a full stack of HTR‐CINE images through the heart was not feasible because of experimental time constraints. Therefore, in the control cohort of mice, the HTR‐CINE sequence was applied at three different short‐axis slice locations and compared with ultrasound measurements of transmitral valve blood flow. The slice locations were defined as follows: basal , mid‐ventricular and apical .2.72; slice thickness, 1 mm; number of slices, 9–12 . Manual segmentation of the LV blood pool in all slices was used to calculate the end systolic volume (ESV), end diastolic volume (EDV), stroke volume (SV) and EF.Parameters of systolic cardiac function were measured using a spoiled, prospectively ECG‐gated, fast low‐angle shot (FLASH) sequence as described in Stuckey et al.2.8k‐space based on the timings of the events recorded by the datalogger  of 1400 times, equivalent to 9.5 min. During this time, all respiration, ECG and RF events were recorded using a Power1401 datalogger in combination with Spike2 software  for retrospective reconstruction. HTR‐CINE images were then created offline in MATLAB  using custom‐made scripts which reconstructed r Figure a. Simulas Figure b. FurtheTime–volume curves were generated by manual segmentation of the LV blood pool. The blood pool volume within a slice was calculated based on the product of the in‐plane voxel area, slice thickness and number of pixels in the segmented region. The first derivative of the time–volume curve was taken to calculate cardiac filling rates. These curves were used to determine the E and A peaks by manual measurement. For further analysis, the volume curves from each of the three slices were averaged together to create a combined curve which represented the whole imaging volume. E and A were also determined from this combined curve and compared with ultrasound.2.92; slice thickness, 1 mm.Myocardial infarct size was measured using a multi‐slice gradient echo IR LGE sequence, described previously.2.10For the assessment of diastolic function, colour B‐mode‐guided, pulsed‐wave, Doppler mode ultrasound was used to measure mitral inflow in an apical four‐chamber view of the heart. E and A peaks were measured from three consecutive heart beats, and the mean E/A ratio was calculated for each animal.2.11σ to the mean μ:The coefficient of variation (CV) is a normalised measure of data variability given by the ratio of the standard deviation CV was used to calculate the variability in the measurements of E/A between repeat trials in the control cohort using both ultrasound and HTR‐CINE MRI. For further comparison, CV was also calculated for measures of systolic function: EF, ESV, EDV and SV.F is the change in estimates of E/A between trials and F¯ is the mean estimate of E/A between trials. Similarly, RC was calculated for measures of EF and SV. For interpretation, RC provides an indication of the change required to observe a difference above variation.Bland–Altman plots were produced to examine the repeatability of E/A estimates using both modalities. The Bland–Altman repeatability coefficient (RC) was calculated for each plot, which represents the 95% confidence interval of the difference in the two trials. RC is given by:Bland–Altman plots were also used to visualise inter‐modality variation. Spearman's correlation coefficient was calculated to examine the level of agreement between inter‐modality measurements of E/A in both the naïve and infarcted cohorts of mice.33.1p = 0.0002) compared with the control animals. EDV was 39% higher (p = 0.019), ESV was more than 200% higher (p = 0.0006) and SV was not significantly different between the cohorts (p = 0.19).Eight control mice and 13 infarcted mice were imaged with standard CINE imaging Videos  and S2 t3.2Figure 3.3p > 0.05, Wilcoxon signed‐rank test).Figure Visual inspection of the raw data Figure b indicatFor comparison, Table Bland–Altman analysis was also carried out to examine the repeatability of E/A measurements Figure . RC for ρs = 0.54, p = 0.04) when comparing ultrasound with basal slices. Furthermore, the bias was small at 2% and the SD of the bias at 15% was the lowest of all the slice positions.Inter‐modality analysis demonstrated that the best agreement was between ultrasound measurements of E/A and basal slices using HTR‐CINE MRI Figure a. SpearmThe variability, repeatability and inter‐modality analysis of E/A measurements indicated that, for subsequent studies, basal slice locations should be used to measure E/A with HTR‐CINE MRI.3.4ρs = −0.88, p = 0.000019).Four weeks after myocardial infarction, 13 mice were imaged using standard CINE imaging, HTR‐CINE imaging  and LGE ρs = −0.75, p = 0.02).However, a broad range of infarct volumes was measured, from 3% to 43%, indicating that surgery was not always successful. Four mice from the cohort were identified as having only mild cardiac impairment, defined as EF > 50% and LGE/LV < 10%, where there was either normal or slightly reduced EF compared with the control cohort, in combination with only minor gadolinium contrast enhancement within the myocardium. Consequently, these mice in the cohort were excluded from subsequent analysis  using ultrasound and basal slice measurements with HTR‐CINE MRI. Figure p = 0.15, Mann–Whitney U‐test). With MRI, a reduction in mean E/A of 29% was observed from 1.32 ± 0.09 in the control group to 0.94 ± 0.11 in the infarcted group. This was above the RC value for MRI  and the difference between groups was significant .E/A ratios were assessed in the infarcted cohort  showed a positive bias (22%): there was a tendency for MRI measures of E/A to be lower than ultrasound measurements. Calculation of Spearman's coefficient  showed that the two modalities were strongly correlated.Bland–Altman analysis of the E/A ratios between the two modalities across the full infarcted cohort , potentially giving a false indication of cardiac impairment based on a human metric of diastolic function.The repeatability of E/A measurements was comparable between modalities in the control cohort of mice. Ultrasound had a slightly lower RC – by 2% – compared with basal HTR‐CINE MRI. For comparison with routinely measured systolic parameters, RC of EF and SV were calculated. EF was much lower (RC = 9%) than E/A, as expected, but SV (RC = 21%) was similar to measures of E/A, illustrating that measurements of diastolic function using both modalities are comparably consistent with well‐established, accepted measures of systolic function.When the three slices were combined to produce a single time–volume curve, CV and RC were higher than both ultrasound and single‐slice HTR‐CINE in a basal location, most probably because the increased variability of the mid‐ventricular and apical slices  is averaged into the measurement.The low variability, strong repeatability and good inter‐modality agreement of HTR‐CINE MRI in a basal location were the determining factors for the use of this slice location when imaging the infarcted cohort. In addition, it made sense to assess diastolic function in this location because changes in the LV filling curves will be caused by impaired, but functional, myocardium, rather than directly related to the extent of akinetic scar tissue within the chosen slice, as would be the case in more apical locations. For these reasons, we recommend that future studies wanting to employ MRI to measure diastolic function in mouse hearts use a slice located as close to the mitral valve as possible, whilst avoiding partial volume effects with the left atrium.The mean E/A ratios measured in the control cohort using a basal slice location for HTR‐CINE MRI were comparable with those determined by other authors. For example, experiments by Coolen et al.In the second study, the two modalities were applied to a cohort of mice with myocardial infarction to examine the performance of both techniques for the detection of diastolic dysfunction. We chose to assess diastolic function in myocardial infarction because we have expertise in this mouse model and it is the most frequently used model of heart disease. The use of this mouse model is a limitation of the current study as ideally it would be most valuable and interesting to examine diastolic dysfunction in other subtler disease models, such as diabetic mouse models in which systolic function is better preserved.The infarcted cohort was imaged with standard CINE imaging as well as IR LGE imaging to determine EF and infarct size. Analysis revealed that the cohort exhibited a range of infarct severities, with some having minimal cardiac impairment; hence, four mice were excluded from the analysis of diastolic dysfunction. On average, infarcted mice exhibited reduced E/A ratios compared with healthy mice. With ultrasound, there was an 11% decrease in mean E/A from 1.36 ± 0.08 in the control group to 1.21 ± 0.11 in the infarcted group. Correspondingly, this still indicates normal cardiac function (E/A > 1.0). With MRI, the mean E/A in the infarcted group was 29% lower at 0.94 ± 0.11, on average suggesting cardiac impairment (E/A < 1.0). These results indicate that HTR‐CINE was able to detect abnormal diastolic function, whereas ultrasound was not able to detect this difference. The reason for this difference may possibly be attributed to the quantification of E/A in different ways by the two modalities; the morphological change measured by MRI may be a more direct measure of myocardial relaxation than ultrasound measurement of blood velocity. These morphological changes may be more pronounced than alterations to flow when impairment is low, such as in the relatively small infarcts used in this study.Alternative MRI methods, including phase contrast velocity encoding of flow across the mitral valveIn summary, this study has shown, for the first time, that HTR‐CINE MRI can measure diastolic function in normal mice with an accuracy and repeatability comparable with the accepted standard of pulsed‐wave Doppler ultrasound. When applied to a mouse model of myocardial infarction, HTR‐CINE MRI detected mild heart failure, whereas measurement with ultrasound did not reach significance.Figure S1 Supporting info itemClick here for additional data file.Figure S2 Supporting info itemClick here for additional data file.Supplementary Video S1: Example standard CINE movie from a basal slice location in a normal mouse. Click here for additional data file.Supplementary Video S2: Example standard CINE movie from a basal slice location in an infarcted mouse. (Supplementary_Video_S2_Infarct_20frames.avi)Click here for additional data file.Supplementary Video S3: Example retrospective HTR‐CINE movie (showing 90 frames through the cardiac cycle) from the same animal and slice location as in Supporting Video S1. Click here for additional data file.Supplementary Video S4: Example retrospective HTR‐CINE movie (showing 90 frames through the cardiac cycle) from the same animal and slice location as in Supporting Video S2. (Supplementary_Video_S4_Infarct_90frames.avi)Click here for additional data file.


Optimal patients characterization in Heart Failure with Preserved Ejection Fraction (HFpEF) is essential to tailor successful treatment strategies.Cardiac magnetic resonance derived T1-Mapping allows for non-invasive quantification of diffuse myocardial fibrosis as extracellular volume fraction (ECV).We aimed to elucidate the diagnostic performance of T1-Mapping in HFpEF by examining the relationship between ECV and invasively measured parameters of diastolic function and investigated the potential of ECV to differentiate between different pathomechanisms in HFpEF.We performed T1-Mapping in 21 patients with HFpEF and 11 patients without heart failure symptoms. Pressure-volume-loops were obtained with a conductance catheter during basal conditions and handgrip exercise. Transient preload reduction was used to extrapolate the diastolic stiffness constant.Patients with HFpEF showed a higher ECV (p = 0.001), an elevated load-independent passive LV-stiffness-constant β (p < 0.001) and a longer time constant of active LV-relaxation τ (p = 0.04). ECV correlated highly with β . After multivariate analysis, ECV remained the only independent predictor of β.Within the HFpEF cohort, patients with ECV > median showed a higher LV-stiffness-constant (p = 0.05) whereas ECV < median identified patients with a prolonged active LV-relaxation (p = 0.01) and a marked hypertensive reaction to exercise due to a pathologic arterial elastance (p = 0.05).Diffuse myocardial fibrosis, assessed by CMR derived T1-Mapping, independently predicts invasively measured LV stiffness in HFpEF. In addition, ECV helps to non-invasively distinguish the role of impaired active relaxation and passive stiffness. It also refines characterization of patients, which represents a prerequisite for any successful therapy in the future.


Biventricular pacing is an important modality to improve left ventricular (LV) synchronization and long-term function. However, the biological effects of this treatment are far from being elucidated and existing animal models are limited and demanding. Recently, we introduced an implanted device for double-site epicardial pacing in rats and echocardiographically demonstrated favorable effects of LV and biventricular (LV-based) pacing modes typically observed in humans. Here, this new animal model was further characterized. Electrodes were implanted either on the right atria (RA) and right ventricle (RV) or on the RV and LV. Following recovery, rats were either used for invasive hemodynamic measurements  or exposed to sustained RV vs. biventricular tachypacing for 3 days. RV pacing compromised, while LV-based pacing modes markedly enhanced cardiac performance. Changes in LV performance were associated with prominent compensatory changes in arterial resistance. Sustained RV tachypacing increased the electrocardiogram QTc interval by 7.9 ± 3.1 ms , dispersed refractoriness between the right and left pacing sites and induced important molecular changes mainly in the early-activated septal tissue. These effects were not observed during biventricular tachypacing (n = 6). Our results demonstrate that the rat is an attractive new model to study the biological consequences of LV dyssynchrony and resynchronization. Compelling evidence indicates that right ventricular (RV) pacing can be detrimental to left ventricular (LV) function. The sequence of electrical activation during RV pacing may largely resemble the activation pattern of left bundle branch block (LBBB)4, and can result in dyssynchronous LV contraction6. In accordance, RV pacing increases the risk for heart failure (HF) even in patients without pre-existing LV dysfunction10.The electromechanical and molecular consequences of various ventricular pacing modes have become a subject of intense interest in recent years due to profound clinical implications11. BiV pacing has been demonstrated to improve contractile performance in patients with dyssynchrony and to improve long-term survival in selected patients2. Although the clinical effectiveness of CRT is remarkable, there are multiple questions concerning dyssynchrony and CRT that remain ill-defined at present. For example, patient vulnerability to HF progression as a result of iatrogenic RV pacing is variable and optimal management of this problem is controversial13. In addition, it is estimated that around 30% of selected patients based on current indications do not benefit from CRT. Clinical data indicate that improvement in dyssynchrony is a prerequisite for obtaining beneficial effects of CRT, but the extent of such improvement may correlates poorly with clinical outcomes14. Although detailed evaluation including assessment of RV dyssynchrony may supplement LV dyssynchrony information and improve outcome prediction15, responsiveness to CRT also appears to involve factors beyond mechano-energetic considerations3. Recent studies exploring the cellular and molecular impacts of CRT in the failing heart indicate a highly complicated picture of cellular and molecular sequence of events, which is still far from being elucidated and which might be the key for better treatment adjustment and prediction of outcome19. Thus, reliable models that support extensive research of the complex biology of dyssynchrony and resynchronization are of paramount importance for obtaining new clinical insights in this field.Cardiac resynchronization therapy (CRT) by means of biventricular (BiV) pacing was developed as a strategy to overcome the deleterious effects of electromechanical dyssynchrony in the failing heart and represents a major advance in HF therapy21. In addition, the ability to induce clinically relevant manipulations such as hypertension, diabetes as well as molecular and genetic modifications, are quite limited in large animal models. While rodents have many such advantages and are already extensively used in HF research22, technical difficulties in electrode implantation have largely prevented proper validation of the effects of various pacing modes in rodents. Two murine studies utilizing single site pacing of RV and M-mode echocardiography have managed to clearly demonstrate dyssynchrony between the septum and the LV lateral wall24. However, single site ventricular pacing is methodologically problematic since it requires comparison to the spontaneous rhythm, which is different from the pacing state not only in ventricular electromechanics but also in beating rate and atrio-ventricular synchrony. Recently, using double site bipolar electrode implantation in combination with electrical recordings and speckle-tracking echocardiography, we managed to characterize for the first time the effects of various ventricular pacing modes on LV electromechanical synchrony in rats25. We found that RV pacing induces marked LV dyssynchrony compared to right atrial (RA) pacing or sinus rhythm. In contrast, LV pacing and, to a greater extent BiV pacing, diminished LV dyssynchrony25. These findings support the notion that rodent cardiac pacing mimics important electromechanical features seen in humans. However, the actual effects of different pacing modes on LV performance and on the myocardial properties of the rodent heart are still unknown. Therefore, in the present study we used pressure-volume (PV) loop recordings to characterize the effects of different ventricular pacing modes on cardiac performance. Next, we compared myocardial properties following application of sustained RV or BiV tachypacing for 72 hours in conscious freely moving rats. Our findings indicate similarities in the effects of various pacing modes to humans, but also demonstrate remarkable effects on arterial elastance, which were not described in humans to a similar extent. In addition, we found that sustained RV tachypacing induces prominent electrical and biochemical changes in myocardial properties compared to BiV pacing, including the activation of JNK in the early-activated myocardium, which was not previously identified in this setting. Overall, our data mark this model as an attractive new tool to study the complex pathophysiology of ventricular dyssynchrony and resynchronization.Current animal studies dealing with dyssynchrony and resynchronization almost exclusively utilize large animals (mainly dogs). Although insights coming from such models are extremely valuable, their highly demanding nature restricts usage for proof-of-principle studies and widespread experimentation at multiple laboratories25. Thus, it is imperative to characterize in details the hemodynamic effects of RV pacing as compared to normally conducted, synchronous contraction. To enable such analysis we implanted pacing electrodes on both the RA and the RV and utilized them to induce either overdrive atrial (A) pacing (synchronous) or sequential atrial and RV (A + RV) pacing (dyssynchronous) with similar beating rate and atrioventricular (AV) coupling. Using conventional ECG analysis we adjusted the AV interval during A + RV pacing to achieve complete RV pacing activation sequence . Moreover, in humans a reduction of Ea during RV pacing might be associated with pacing-induced mitral regurgitation33. Thus, the elevated Ea we observed during RV pacing implies absence of RV pacing-induced mitral regurgitation in our model. Indeed, we did not detect mitral retrograde flow waves during any of the overdrive pacing modes (n = 5). In addition, we did not notice acute changes in left atrial diameter between the different ventricular pacing modes .An additional important finding was a prominent increase of Ea during A + RV pacing and a further increase during RV-only pacing Table . Since p25. A typical example of obtained electrocardiograms is shown in Fig. Following the above analysis of RV pacing-induced dyssynchrony relative to synchronous pacing, we next used implanted RV and LV pacing electrodes to compare the hemodynamic effects of various ventricular pacing modes. ECG recordings confirmed the previously described effects on QRS duration and morphologyP-V loop recordings indicated profound differences in LV hemodynamic performance, when LV and BiV pacing were compared with RV pacing Fig. . LV systIn an attempt to further clarify the mechanisms leading to the marked differences in LV performance between RV pacing and LV-based pacing modes, inferior vena-cava occlusion experiments were performed. Under our standard experimental conditions without mechanical ventilation, these attempts were challenging and largely failed to induce meaningful curves that could be properly analyzed. Supplemental Fig. Following detailed analysis of the acute consequences of various pacing modes, we next utilized our model to examine for the first time, the effects of sustained RV tachypacing vs. BiV tachypacing in freely moving rats. At baseline, there were no differences between the RV-paced and BiV-paced groups in any of the measured electrophysiological parameters including spontaneous corrected QT interval (QTc-NSR), paced QT interval during RV site pacing and LV site pacing, epicardial activation time during pacing of both sites and VERP during pacing of both sites.RV tachypacing for 72 hours significantly prolonged the QTc-NSR relative to baseline, a phenomenon which was not detected following BiV tachypacing Fig. . AnalysiTo further elucidate the electrophysiological details, we analyzed epicardial activation time and VERP during right (Rt.) site pacing and Lt. site pacing. Epicardial activation was not affected by the different pacing modes Fig. . However23. Analysis of phosphorylated ERK, P38 or AKT did not reveal differential effects between the animals exposed to the different pacing modes  and late-activated  parts of the mid-LV were analyzed focusing specifically on molecules and signals that were previously implicated in the pathophysiology of electromechanical dyssynchronyLevels of Cx43 were also evaluated following RV vs. BiV pacing. While expression appeared to be globally increased in the tachypaced animals relative to shams, it did not consistently vary between the different pacing modes  we found that A + RV pacing did not influence measures of preload  of the rat heart. Moreover, considering the unchanged epicardial activation time in both groups, the observed differences in paced-QT during LV site pacing also support prolongation of APD in the RV free wall. Although our current analysis cannot determine the VERP in the early-activated septal part of the LV, we may speculate that it is also prolonged and contributes to the global increase in non-paced QT following RV tachypacing. Regional changes of VERP in the RV paced rats are somewhat reminiscent to published data in the dog model of LBBB where such changes were related to regional differences in load as well as to the extent of myocardial stretch applied at different time points during the action potential23. In contrast to Bilchick et al.23, here we could directly compare between RV-paced tissue and BiV-paced tissue, under similar beating rate and similar AV synchrony, a mission which is impossible using single site pacing methodology. The most important and somewhat unexpected finding here was a differential effect of RV tachypacing on JNK signaling, in contrast with P38, ERK and AKT previously implicated in the myocardial response to dyssynchrony in the dog heart3. It will be important to further explore whether these discrepancies reflect species dependent differences, or alternatively, it might reflect temporal variations due to the relatively short period of pacing we used here in comparison with the 3–6 weeks period applied in the dog model3. In any case, considering the fact that JNK is a stress-activated protein kinase with clear importance in the myocardium54, this new finding and its implications on the pathophysiology of myocardial dyssynchrony should be further explored in details. It is for example known that JNK is a major regulator of cardiac KChIP2 gene expression, and activation of JNK can diminish the transient outward K+ current (Ito) by transcriptional down-regulation of KChIP255. Whether such mechanism may contribute to differential changes in APD in the RV-paced rat heart is an important possibility that might be explored based on the current findings.Our biochemical results comparing myocardial tissue from the septal wall and the lateral wall of the LV, also support differential effects of RV pacing on the early-activated and late-activated regions as previously suggested in the mouse heart3. Moreover, by using rats it should be rather straightforward to combine our model with other insults leading to myocardial dysfunction such as hypertension, diabetes mellitus, high output failure and more. Further echocardiography regional dyssynchrony assessment in parallel with ventricular arrhythmias substrate evaluation56, is another important future direction. In summary, our current findings support the notion that the instrumented rat model is an important new advance in this field of research and may be used to shed light on fundamental effects of dyssynchrony and resynchronization on the tissue level.Other observed changes in the RV-paced rats including CAMKII activation and increased expression of osteopontin can reflect the profound effects of this dyssynchronous mode of tachypacing on the rat myocardium as opposed to BiV tachypacing. Thus, we may expect that with further prolongation of the tachypacing period profound differences in cardiac function would be noted between animals exposed to RV tachypacing and those exposed to BiV tachypacing. This may lay the foundation for a rat model, which is rather similar to the dog model of dyssynchronous heart failure induced by tachypacing in combination with LBBBThe study was carried out in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. All the experiments reported in this study were approved by the institutional ethics committee of Ben-Gurion University of the Negev, Israel . Adult male Sprague-Dawley rats were obtained from Harlan Laboratories . The animals were kept under standardized conditions throughout the study, according to home office guidelines: 12:12 light:dark cycles at 20–24 °C and 30–70% relative humidity. Animals were free-fed autoclaved rodent chow and had free access to reverse osmosis filtered water. At the end of the experiments animals were sacrificed by extraction of the heart under deep Nembutal-induced anesthesia.57. Briefly, the electrical connections to the epicardial surface were done using miniature-bipolar hook electrodes that were designed by our group for various in-vivo electrophysiological applications in rodents58. Each electrode contains a distal head with two sharp tungsten pins that are curved and isolated by insulted coating up to their tips. By means of small lateral thoracotomy the electrode can be fixed on the selected epicardial surface without the need for additional suturing. The implantable device is composed of an 8 pin ‘female’ connector that is attached by highly flexible insulted electrical wires  to a set of two miniature-bipolar hook electrodes. Additional electrodes for peripheral pseudo-ECG measurements are also implanted subcutaneously. Electron beam radiation is applied for sterilization of the device before its use. For device implantation rats (250–320 g) were anesthetized  and mechanically ventilated. The animals were placed on a warmed heating pad and under sterile conditions the two miniature-bipolar hook electrodes were implanted on the desired sites. Following chest closure the 8-pin ‘female’ connector was exteriorized through the skin of the back. Postoperative recovery and analgesia were done as described previously25. Buprenorphine (0.1 mg/Kg) was given by subcutaneous injection during immediate recovery and every 24 hours during the first 3 days. In addition, Dipyrone (400 mg/500 ml) was added to the drinking water during the first 3 days. The animals were monitored on a daily basis for signs of stress or inappropriate weight loss, according to guidance from the Ben-Gurion University veterinary services  #A5060-01, and fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)).The implantable device and the surgical technique that were utilized to permanently locate two bipolar-electrodes in predetermined epicardial locations were previously described in detail25. 2. Comparison between the effect of sustained RV tachypacing and BiV tachypacing (600 BPM) applied for 72 hours (n = 14). In section #1 hemodynamic measurements were initially done in animals implanted with right atria (RA) and RV electrodes (group A) to fully characterize the effect of RV pacing with and without optimal atrio-ventricular (A-V) coupling (n = 8). Next, electrodes were implanted on the RV and LV (group B) to directly compare between the different ventricular pacing modes using conventional P-V loop recordings (n = 8), inferior vena-cava occlusion studies  and echocardiographic evaluation directed towards mitral regurgitation and atrial dimensions assessment during the different pacing modes (n = 5). In part #2 animals were divided into three groups: shams, which were connected to the system without pacing (n = 2), sustained RV pacing (n = 6) and sustained BiV pacing (n = 6).Overall 39 successfully implanted rats were evaluated in this work. The study contained two principle parts: 1. Acute hemodynamic measurements during various pacing modes (n = 23). In this section each animal served as its own control and the effects of various pacing modes were compared in each animal as previously done for strain analysis2 through a face mask. Body temperature was rectally monitored and maintained at 37 ± 0.5 °C by a circulating water warming pad. Electrical stimulation (2 ms square pulses) was applied using isolation units  at a double diastolic threshold. A Labview 7.1 based program previously developed in our laboratory57 was used to control electrical stimulation as well as ECG recordings  through an A/D converter  as previously described25.Rats were evaluated 6–8 days after implantation of the pacing device. Animals were anesthetized by 3% isoflurane in an induction chamber followed by constant administration of 2% isoflurane with supplemental O61. Based on previous echocardiographic measurements from our laboratory under isoflurane anesthesia we estimated stroke volume of 0.9 μl/g of body weight for each animal. While this estimation might be somewhat biased from the absolute values, our analysis focused on the comparison of the effects of different pacing modes in each animal. Thus, the relative changes between the pacing modes were the main focus of our study. Following equilibration, pressure–volume curves were acquired during various pacing modes using continuous override pacing at a 150 ms cycle length (CL). The P-V loop acquisition protocol was as follows: Following optimal positioning of the catheter in the LV, it was fixed in place and LV P-V loops (1–2 minutes each) were sequentially recorded in sinus rhythm followed by override pacing at the different pacing sites. In group A the modes of the pacing were: (1) RA pacing alone; (2) sequential RA-RV pacing at the longest AV interval producing a right ventricular activation sequence without fusion as confirmed by QRS morphology , ejection fraction (EF), stroke work (SW), the maximal slope of the systolic pressure increment (dP/dtmax), the diastolic pressure decrement (dP/dtmin), and the time constant of isovolumic relaxation (Tau). At the end of all P-V loop recordings animals were sacrificed and correct positioning of the epicardial electrodes was confirmed by post-mortem operation. For description of inferior vena-cava occlusion attempts under RV vs. BiV pacing see supplemental methods.In each animal the right common carotid artery was exposed and a 1.9-Fr pressure-volume (P-V) catheter  was inserted into the right common carotid artery and passed in a retrograde fashion through the aortic valve into the LV to monitor pressure and volume as well as admittance magnitude and phase angle signals in the LV. Data were acquired using a ADI LabChart acquisition and analysis software which was also used for offline analysis. Signals were acquired at a sampling rate of 1,000 Hz using an Advantage PV system . The steps involved in the setup and use of the Advantage system, i.e., catheter calibration and measures of myocardial conductivity and permittivity were done as previously described in the literatureogy Fig. ; (3) RV 25 with a Vivid 7 echocardiography system  and 10S probe. Following optimal positioning of the transducer in an apical four chamber view, it was fixed in place by the operator, while clips were sequentially recorded during override pacing (150 ms Cycle length) under the different pacing modes . Presence or absence of mitral regurgitant jet was assessed with 2D color Doppler and continuous-wave Doppler. Maximal atrial diameter in the apical four chamber view was also evaluated during the different pacing modes.Analysis was done under isoflurane sedation (1%) as previously described57. Pacing was done using optically isolated units . Pseudo ECG and epicardial signals were recorded using conventional amplifier . The animals were allowed to adapt for 24 h in the cage. On the 7th postoperative day, baseline pseudo ECG recordings were recorded and measurements of ventricular effective refractory period (VERP) were evaluated through each pacing electrode (RV and LV). VERP was determined at twice-diastolic threshold as the longest S1-S2 interval that failed to generate a response. The programed stimulation protocol included ten S1 stimuli at 100-ms cycle length, followed by S2 decremented in 2-ms intervals. QT and epicardial activation time measurements were done as previously described25. QTc was calculated using normalized Bazett’s equation adapted for rats: QTcn − B = QT/(RR/f)1/2, where f is the normalization factor according to the basal RR duration (150 ms for rats)62.On the 6th postoperative day animals were placed in dedicated pacing and recording cages where the back connector was linked by an elastic cable to the pacing and recording apparatus as previously describedAfter baseline measurements, continuous RV pacing (n = 6) or BiV pacing (n = 6) was initiated at a 100 ms CL. Confirmation of effective pacing was continuously monitored through online pseudo ECG recordings. For the BiV pacing group we routinely confirmed effective pacing through each of the pacing channels (RV and LV) at least twice daily. At the end of 72 hours of pacing all electrophysiological parameters were re-evaluated, before the animals were sacrificed.63. Membranes were incubated with primary antibodies including: rabbit anti-phospho-ERK 1/2 ; rabbit anti-phospho-p38 ; rabbit anti-phospho-JNK ; mouse anti-total-JNK , rabbit anti-phospho-CaMKII ; rabbit anti-total-CaMKII , rabbit anti-phospho-Akt Ser473 ; mouse anti-osteopontin ; rabbit anti-Connexin 43 . GAPDH was evaluated using rabbit anti-GAPDH  and served as loading control. Filters were extensively washed in TBS-T and then were incubated with horseradish peroxidase-conjugated secondary antibody. Secondary antibody was a species-specific horseradish peroxidase-conjugated goat anti-rabbit  or goat anti-mouse . Bands were visualized by using the ECL system  and were quantified with computerized densitometry and ImageJ (version 1.24) software. Densitometric values were reported after normalization for gel-loading differences and relative to the average value obtained from protein extracts of sham-operated control rats. For description of real-time QT-PCR analysis and histological analysis of connexin43 see supplemental methods.All animals exposed to 72 hours of RV pacing (n = 6), BiV pacing (n = 6) or sham-operation with no pacing (n = 2) were sacrificed and tissue samples from the septum (early activated) and the free wall (late activated) of the LV were snap frozen in liquid nitrogen. Protein lysates were obtained in RIPA buffer containing protease and phosphatase inhibitors and prepared for immunoblot analysis as previously describedP < 0.05. Unless otherwise stated p-values are displayed graphically as follows: *p < 0.05, **p < 0.01, ns = not significant.Values are expressed as means ± SE. In part #1 comparison between the different pacing modes was done utilizing 1-way ANOVA of repeated measures and Tukey multiple comparisons post-test. Inferior vena-cava occlusion analysis data was compared using Wilcoxon rank test. In part #2 comparisons were done using paired or unpaired t-test as required. For n of less than 6 or parameters that are not normally distributed non-parametric testing was performed. The criterion for significance was set at Supplementary data


Intraventricular hydrodynamics plays an important role in evaluating cardiac function. Relationship between diastolic vortex and left ventricular (LV) filling is still rarely elucidated. The aim of this study was to evaluate the evolution of vortex during diastole in hyperthyroidism (HT) and explore the alteration of hydromechanics characteristics with sensitive indexes.P), in different diastolic phases  were calculated and analyzed.Forty-three patients diagnosed with HT were classified into 2 groups according to whether myocardial damage existed: simple hyperthyroid group  and thyrotoxic cardiomyopathy . Twenty-seven age- and gender-matched healthy volunteers were enrolled as the control group. Offline vector flow mapping (VFM model) was used to analyze the LV diastolic blood flow patterns and fluid dynamics. Hemodynamic parameters, vortex area (A), circulation (C), and intraventricular pressure gradient (ΔP < .05). Compared with the control group, the vortex size and strength, intraventricular pressure gradient during early and mid-diastole were higher in HT1 and lower in HT2 (P < .05). And in late diastole, the vortex size and strength, intraventricular pressure gradient of HT2 became higher than those of the control group (P < .05). Good correlation could be found between CE and E/A (P < .05), CM and ΔPM (P < .01), CL and FT3 (P < .05).HT2, with a lower E/A ratio and left ventricular ejection fraction (LVEF), had a larger left atrium diameter (LAD) compared with those of the control group and HT1 (VFM is proven practical for detecting the relationship between the changes of left ventricular diastolic vortex and the abnormal left ventricular filling. Intraventricular vortex formed by the morphology and function of the cardiovascular system can reveal the global diastolic function of LV and the exceptional adaptability of cardiovascular system for maintaining the blood circulation relatively constant under a wide range of workload.Previous studies on left ventricle (LV) filling dynamics focused on single-point flow velocity measurements by Doppler echocardiography. However, the single-point velocity measurements cannot accurately evaluate the global diastolic function of LV because the intraventricular velocity profile is complex.,5 CMR displays 3-dimensional (3D) chamber flow fields in a variety of visualization methods via electrocardiogram (ECG) and respiratory gating, but it has not yet been routinely used in clinical practice due to long duration of the test, a rather high cost, and a low temporal resolution. Compared with CMR, CE-PIV has superior temporal resolution. It uses moving tracks of ultrasound microbubbles to represent the distribution of the blood flow field, thereby providing a more accurate calculation of the flow velocity. However, the test requires contrast media, and the range of velocities that can be measured is limited. VFM visualizes cardiovascular blood flow in vectors based on color Doppler superimposed on speckle tracking—a method for tracking cardiac wall motion. Improvements have been made in new VFM to allow for more accurate and stable calculation of hemodynamic parameters and flow velocity near the wall. It is considered to be one of the representative methods for visualization of blood flow in vivo that can compete with CMR and CE-PIV.,9Computational fluid dynamics (CFD) and particle image velocimetry (PIV) have been applied in some new technologies for the assessment of cardiac function that have expanded our options to visualize and analyze the complex intracardiac flow. Among them, cardiac magnetic resonance (CMR), CE-PIV technique combined contrast echocardiography (CE) and PIV, vector flow mapping (VFM) based on color Doppler flow imaging (CDFI) and speckle tracking are the principal methods that are currently used in the assessment of patients in the very early stage of cardiovascular disease or for investigating complex geometry after cardiac surgery. The evolution of the LV diastolic vortex in HT at different stages might change with the volume load, cardiac structure, and function. This study attempted to detect the LV hemodynamics in HT using VFM and investigate the relationship between the diastolic vortex field and abnormal LV filling.Excessive secretion of thyroid hormones in patients with hyperthyroidism (HT) produces cardiotoxicity.22.1Sixty patients diagnosed with HT between March and December 2014 in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China were randomly recruited in this study. Nine patients were excluded due to poor image quality, and 8 cases were excluded due to cardiac arrhythmia. Forty-three patients were involved in the study finally. Of them, 22 (8 men and 14 women) who were referred to the cardiologist and identified with dilated cardiomyopathy were assigned to thyrotoxic cardiomyopathy group (HT2), aged between 21 and 63 years (mean 42.00 ± 13.01 years). The remaining 21 patients (9 men and 12 women) were assigned to simple HT group (HT1), aged between 18 and 56 years (mean 35.45 ± 10.34 years). In addition, 27 gender- and age-matched healthy volunteers (15 men and 12 women) during the same period in our hospital were enrolled as the control group, aged between 20 and 56 years (mean 40.62 ± 13.08 years). presence of classical clinical symptoms and physical signs of HT; laboratory criteria: thyroid stimulating hormone (TSH) < 0.5 μU/mL , free Triiodothyronine (FT3) > 9.15 pmol/L , and/or free Thyroxine (FT4) > 25.47 pmol/L ; exception of other organic heart diseases and symptom of thyrotoxic cardiomyopathy. Thyrocardiac disease is defined as the presence of congestive heart failure, angina pectoris, or both, in a patient with hyperthyroidism. The study was approved by the ethics committee of Tongji Medical College, Huazhong University of Science and Technology. All study subjects provided written informed consent.Diagnostic criteria for HT2.2Transthoracic echocardiography was performed on all subjects using Aloka Prosound F75 scanner equipped with a frequency 2 to 4 MHz transducer (UST5415). ECG was simultaneously recorded to determine the cardiac phase. Left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), transmitral peak E and A velocities  were measured at the parasternal LV long-axis view. LV ejection fraction (LVEF) was calculated by the modified biplane Simpson method. Standard 2D color flow Doppler dynamic images in 3 consecutive beats were recorded from the apical long-axis view. The scanning width, imaging depth, and spatial temporal settings were optimized to achieve the highest possible frame rate. Doppler velocity scale varied from 50 to 60 cm/s in this study, and the frame rate was set at 25 frames per second for all subjects. All recordings were stored digitally and analyzed offline.All the stored raw data were processed on offline VFM workstation . As the boundary of flow in LV was outlined, the system automatically traced the flow signals and calculated the velocity vector. Diastole was determined based on synchronous ECG (from the end of the T-wave to the onset of the Q-wave). Early diastole (rapid filling), mid diastole (slow filling), and late diastole  were defined depending on the flow rate-time graph of mitral valve (MV) and behavior of valve.V) (ΔV = velocity of MV − velocity of cardiac apex). Then intraventricular pressure gradients in different filling phases  can be calculated according to the formula ΔP = 4 × ΔV2.A sampling line from the endocardium of cardiac apex to MV was drawn under the guidance of streamline to measure the intraventricular velocity gradient , only the one near the anterior leaflet was analyzed.P and C for both filling phases were analyzed.Observer repeated the same measurements in randomly selected 12 cases after 1 week, and another independent observer repeatedly performed measurements on these 12 subjects. Then, intra- and interobserver reproducibility of Δ2.3P < .05 was considered statistically significant.SPSS Statistic software  was used to perform statistical analysis in the study. Continuous data were expressed as mean ± SD (x ± s). Clinical characteristics and hemodynamic variables were compared using one-way analysis of variance (ANOVA) followed by Dunnett contrasts against the control group, when appropriate. Relationships between vortex variables and clinical, echocardiographic characteristics were evaluated by Pearson linear regression analysis. Intra- and interobserver variability values were analyzed by Bland–Altman bias plots. The mean and intraobserver and interobserver differences were plotted against the mean of 2 measurements, with 95% of the data points recommended to lie within ± 2SDs of the mean difference. 33.1P > .05). HR, SBP, FT3, and FT4 were higher, and TSH was lower in patients compared with those of the controls (P < .05). Patients in HT1 had the shorter course and faster HR than those in HT2. Compared with controls and HT1, HT2 showed significant increases in LAD, LVEDD, and A peak, along with E peak, E/A ratio, and LVEF reduced (P < .05). LVEF in HT1 was higher than that of controls, and there were no significant differences in LAD, LVEDD, E peak, A peak, and E/A ratio between them.The clinical data and hemodynamic variables are described in Table 3.2PE, ΔPM, and ΔPL). In addition, intraventricular pressure gradients during early and mid-diastole (ΔPE and ΔPM) in HT2 were lower than those in controls and became notably higher than controls at the end of diastole (ΔPL) (P < .05).Table 3.3In the control group, a strong inflow jet directed almost straight to the apex with a minor zigzag pattern and 2 asymmetric vortices appeared behind the MV leaflets after MV opening during early diastole. The one near the anterior side was larger. These 2 vortices continued their development during the period of rapid filling, reaching their full development when the E wave approached its peak (E peak). During slow filling, E wave deceleration occurred, and pressure across the MV decreased. Direction of the LV blood flow changed from apex to LV outflow, and the streamlines of inflow blood became rotated turbulently. These 2 vortices evolved into a single large one that was loosely concentrated, progressing toward the apex with the vortex area and circulation continuously growing. Followed by a late filling of atria contraction, the early filling vortex was weakened by the A wave onset, causing the late filling jet (A peak) to destroy the relatively apically located large vortex, creating another 2 symmetric and smaller vortices close to the mitral tip Fig. .P < .01)  from early to mid-diastole, but became significantly higher than controls during late filling , and negatively correlated with DBP . CM was closely correlated with ΔPM . CL was positively correlated with FT3 and FT4 . There were positive correlations between ΔPE and E peak , ΔPM and E/A ratio , ΔPL and A peak .Relationships between vortex variables and clinical, echocardiographic characteristics evaluated by Spearman linear regression analyses are shown below. C3.5Results of inter- and intraobserver analysis for the assessment of diastolic intraventricular pressure gradients and circulation are presented in Table 3.6 With long-lasting excessive thyroid hormone, functional and morphological abnormalities occur in the heart, and compensatory cardiac hypertrophy exists which ultimately leads to heart failure. Congestive heart failure is the well-recognized complication of HT. Research showed that diastolic dysfunction appeared earlier in patients with hyperthyroid heart failure than those with hypothyroid heart failure. However, pathologic studies of HT generally believed that thyroid hormone enhances LV diastolic filling.,18 Indices of conventional echocardiography are vulnerable to the geometry of the heart, HR, and load. Thus, they cannot objectively reflect the changes in diastolic function. Hydromechanics research demonstrates that intraventricular vortex reflects the LV functional status. Study about the relationship between LV filling and diastolic vortex in patients with HT from the perspective of fluid mechanics is rare. In this paper, we attempted to observe the characteristics of diastolic vortex in patients with HT using VFM to objectively reflect the dynamic changes in LV diastolic function.HT is a common metabolic disorder with prominent cardiovascular manifestations. The direct toxic effect of thyroid hormone and indirect action via catecholamine on the cardiovascular system can lead to a typical hyper-dynamic circulatory state which manifested as accelerated HR, increased blood volume, increased stroke volume (SV), increased LVEF, and high cardiac output. These changes were mainly due to the excess thyroid hormones that directly or indirectly affected the heart via sympathetic nerve and improved the sensitivity of myocardial β receptors to catecholamine, which resulted in cardiac sympathetic nerve hyperactivity. Therefore, the heart was in a hyperdynamic circulation state with high cardiac output, accelerated HR, and increased contraction function.This study showed that patients in HT1 experienced accelerated HR and increased LVEF, which were consistent with the previous studies. Steatosis and hypertrophy existed, LV geometric configuration and function changed, which manifested as cardiac enlargement, reduced cardiac systolic and diastolic function.In this study, patients with thyrotoxic cardiomyopathy had significantly longer courses than simple HT. LVEDD and LAD were higher, LVEF and E/A ratios were lower in HT2 than those in controls and HT1. These were due to the progression of the HT course. Excess thyroid hormones enhanced the calcium and glucose absorption of cardiomyocytes, accelerated metabolism, and increased the proportion of myocardial oxygen consumption. When overloading exceeded the maximum steady state, a relative myocardial ischemia and myocardial damage occurred.,18 Then the larger, stronger vortex was generated in cardiac chambers. Enhanced diastolic vortex in LV can increase positive pressure and assist filling by eliminating convective deceleration load. And the higher intraventricular pressure gradient in patients with simple HT is helpful to pull blood from left atrium into LV more efficiently for adapting the increased circulating blood volume. Martínez-Legazpi et al found that diastolic vortex can assist LV filling without energy consumption and negative impact on intraventricular diastolic pressure distributions. Such vortex formation may be beneficial in efficient MV closure, efficient diastolic filling, minimizing kinetic energy loss, preventing thrombus formation, and maintaining normal diastolic function.,25 The difference in E/A ratio between HT1 and controls had no statistical significance, suggesting that diastolic vortex might be more sensitive in evaluating LV filling capacity. Mintz et al found the enhanced left ventricle diastolic function appeared in a group of newly diagnosed and untreated HT patients, and believed that it has something to do with the early state of thyrotoxic cardiac damage. Additionally, vortices dissipate flow energy by viscous  effects, the dissipated loss increased when the vortical change speed accelerated (heart rate elevated). Therefore, there is a cascade of energy dissipated as heat in patients with HT, under the state of hyperdynamic circulation, which provide a favorable milieu for the development of heart failure.Analysis of flow field parameters showed that the vortex size and strength in these 3 diastolic phases, intraventricular pressure gradient in early and mid diastole of HT1 were higher compared with the control group and HT2, which might be associated with the improved LV filling capacity and the hyper-dynamic circulatory state. Thyroid hormones’ indirect action on the cardiovascular system accelerates HR, reduces peripheral vascular resistance, and enhances cardiac output. In addition, the direct effect of thyroid hormones on heart enhances myocardial relaxation by upregulating expression of the sarcoplasmic reticulum calcium-activated ATPase (SERCA) and downregulating expression of phospholamban. believed that ventricular volume load increasing could only be manifested as slight reduction in early relaxation and significant increase in late compliance, which corresponded to the results of diastolic function and vortex field in patients with thyrotoxic cardiomyopathy. In addition, the intra- and inter-observer reproducibility of VFM parameters was excellent. VFM could be used for accurate and visual evaluation of LV diastolic function and vortex field distribution in patients with HT.The vortex size and strength, intraventricular pressure gradient in HT2 were lower compared with controls in early and mid diastole and then became higher than those of controls in late diastole. We speculated that the change of hydrodynamics might be linked to diastole dysfunction. The lasting stimulating of thyroid hormones on cardiomyocytes in patients with thyrotoxic cardiomyopathy resulted in myocardial necrosis and myocardial interstitial fibrosis, which weakened LV relaxation in early diastole. LV diastole results from the simultaneous and complementary action of relaxation and compliance respectively generated in early and late filling. The vortex generated in early diastole was too weak to ensure complete intraventricular filling. The compliance and vortex in late diastole then showed a compensatory increase during late diastole. Moreover, accelerated heart rate leads to a relative increase in the atrial contribution to left ventricular filling due to a shortened diastolic filling time. Decreased LV filling volume and increased filling pressure during early diastole may cause the syndrome of congestion in pulmonary and systemic circulation. At this time, atria systole was enhanced in patients with thyrotoxic cardiomyopathy for removing the residual blood volume in atrium and compensating the increased circulating volume, which significantly enlarged and strengthens the late diastolic vortex in LV chamber. PasipoularideE was positively correlated with E values and E/A ratio, indicating that the vortex in LV was related to diastolic function during early diastole. On the other hand, the abnormal vortex during active filling suggested that the diastolic dysfunction exists. CM was positively correlated with ΔPM, and ΔPM was positively correlated with E/A ratio, showing the close correlation between vortex and intracardiac positive pressure during filling. By increasing positive pressure gradient and reducing convective deceleration load, vortices contribute to ventricular filling. As LV was a relatively closed chamber when MV closed during mid-diastole, ventricular pressure was not subject to left atria pressure and only associated with intraventricular vortex. CL was positively correlated with FT3 and FT4, which indicated that the ventricular vortex was closely bound up with the level of thyroid hormones during left atria systole in a certain range. The excess thyroid hormones effected the relaxation of LV, which cause the left atrial pressure and vortex during late diastole rising to compensate for the rising volume load.Correlation analysis showed that CThere were certain limitations in our study. First, manual correction for aliasing was performed in the present study, as double or higher aliasing cannot be corrected by VFM, which may underestimate the velocity. Second, color flow frame rate is slightly low. Thus, there might be deviation in the analysis of diastolic phases. Third, we failed to obtain the left atrium-ventricle pressure difference by cardiac catheterization. Therefore, the relationship between the diastolic vortex and the atrium-ventricle pressure difference could not be analyzed directly. More efforts need to be exerted in the future studies. And finally, the vortex is a 3D entity, and fluid evaluation in 3D would be desirable to ensure accurate determination of the evolution of vortex. At present, however, VFM has not been converted to 3D.In summary, our study showed that LV flow field can give insights into abnormal diastolic filling in HT. For patients with simple HT, the improved LV diastolic function and high-performance vortex contribute to accommodating the hyper-dynamic circulatory state. In patients with obvious thyrotoxic cardiac damage, the reduced vortex during early and mid-diastole is partially related to relaxation dysfunction, and the increased vortex during late diastole is about the compensatory raising of volume load.


Severe pulmonary regurgitation (PR%) and consequent right ventricular (RV) enlargement are observed features in repaired tetralogy of Fallot (ToF). Due to ventricular interactions, the shape and function of the left ventricle (LV) can also be affected. It has been shown, for instance, that ToF patients exhibit reduced longitudinal strain as a possible sign of LV dysfunction, despite normal ejection fraction (EF). Literature has also indicated that LV dysfunction in ToF can have prognostic value. This study thus sought to investigate ventriculo-arterial coupling on the systemic side and LV shape by means of CMR analysis.A retrospective cohort of ToF patients (n = 201) was analysed. Patients with late repair (>1 year) and BT/Waterston shunts were excluded. All patients had CMR examination. The phase contrast flow sequences in aortic position were analysed to derive aortic wave speed and wave intensity, the latter defined as the product of velocity differentials with fractional changes in aortic area and taken as an indicator of the working efficiency of the LV and ventriculo-arterial coupling. Wave intensity data were stratified according to PR% and analysed accordingly. Additionally, multivariable regression analysis was performed on the whole cohort, assessing the effect of PR%, aortic distensibility, sex and age on wave intensity magnitude. Furthermore, short axis stack sequences of the RV and LV were used as inputs for statistical shape analysis, building a statistical shape atlas for both RV and LV for different PR% .Functional CMR data revealed enlarged RV (p < 0.001) with severe PR%, as expected, while LV volume did not change significantly across the strata. LVEF was significantly lower for severe PR% , albeit still in the normal range. Wave intensity magnitude was significantly (p = 0.01) lower in the presence of PR%, indicating less favourable aortic ventriculo-arterial coupling; however it did not progressively decrease with increasing PR%. Patients with increasing PR% severity did exhibit stiffer aortas (p = 0.01) according to wave speed results and a multivariable regression model showed that aortic distensibility was in fact the only significant (p = 0.001) predictor of wave intensity magnitude, particularly of the forward compression wave, typically considered as a surrogate for ventricular contractility. Statistical shape atlases were also successfully calculated, providing additional insight into RV and LV shapes.Wave intensity analysis and statistical shape analysis confirm changes in RV and LV function and shape in patients with repaired ToF. Patients with some degree of PR%, even mild, exhibited lower forward compression wave in the aortic wave intensity profile, suggesting unfavourable ventriculo-arterial coupling, but analysis revealed that reduced aortic distensibility is the main predictor for changes in LV efficiency.


The diagnosis of acute cardiac rejection (AR) still requires invasive technique with endomyocardial biopsy (EMB) which has important risks and limitations.Cardiac Magnetic Resonance (CMR) with recently T2 and T1 mapping is a promising technique for characterizing myocardial tissue.The purpose of the study was to evaluate T2, T1 and extracellular volume (ECV) quantification as novel tissue markers to diagnose acute cardiac rejection.CMR was prospectively performed in heart transplant patients within 6 ± 13 days of routine EMB and before acute rejection therapy. Images were acquired on a 1.5 Tesla scanner including T2 mapping (T2 prepared-SSFP) and T1 mapping using a modified look locker inversion recovery sequence (MOLLI) at basal, mid and apical level in short axis view.th and the 95th percentiles.T2 and T1 values were measured before and 15 minutes (for T1 mapping) after contrast administration. The results are expressed by the median and the 5Twenty five patients (age 56 ± 14 years) were included providing 38 comparisons CMR/EMB. Acute rejection  was diagnosed in 11 patients.Patients with AR had significantly higher global T2 values at 3 levels . The area under the curve (AUC) for each level was: 0.83; 0.58 and 0.77 respectively.Patients with AR had significantly higher ECV at basal and median level: 35% [33-39] vs 27% [25-31] P = 0.003 and 33% [28-39] vs 27%[24-31], P = 0.025 respectively. The AUC for each level was; 0.85 and 0.75 respectively.The sensitivity, specificity and diagnosis accuracy for basal T2 (cutoff : 57.7 ms) were 70%, 96% and 79% respectively; basal ECV: (cutoff 31.2%) 89%, 77% and 81% respectively. The best AUC (0.88) was obtained when we combined basal T2 and basal ECV.In heart transplant patients, a combined CMR approach using T2 mapping and ECV quantification provides a high diagnostic accuracy for acute rejection diagnosis and could potentially decrease the number of routine EMB. Further studies are required to confirm these data.


Native T1 mapping is a cardiovascular magnetic resonance (CMR) technique that associates with markers of fibrosis and strain in hemodialysis patients. The reproducibility of T1 mapping in hemodialysis patients, prone to changes in fluid status, is unknown. Accurate quantification of myocardial fibrosis in this population has prognostic potential.Using 3 Tesla CMR, we report the results of 1) the inter-study, inter-observer and intra-observer reproducibility of native T1 mapping in 10 hemodialysis patients; 2) inter-study reproducibility of left ventricular (LV) structure and function in 10 hemodialysis patients; 3) the agreement of native T1 map and native T1 phantom analyses between two centres in 20 hemodialysis patients; 4) the effect of changes in markers of fluid status on native T1 values in 10 hemodialysis patients.r = 0.682;P = 0.03) representing altered fluid status between scans. There were no correlations between change in native T1 between scans (ΔT1) and ΔLVEDV or Δweight (P > 0.6). Linear regression confirmed ΔT1 was unaffected by ΔLVEDV or Δweight (P > 0.59).Inter-study, inter-observer and intra-observer variability of native T1 mapping were excellent with co-efficients of variation (CoV) of 0.7, 0.3 and 0.4% respectively. Inter-study CoV for LV structure and function were: LV mass = 1%; ejection fraction = 1.1%; LV end-diastolic volume = 5.2%; LV end-systolic volume = 5.6%. Inter-centre variability of analysis techniques were excellent with CoV for basal and mid-native T1 slices between 0.8–1.2%. Phantom analyses showed comparable native T1 times between centres, despite different scanners and acquisition sequences . For the 10 patients who underwent inter-study testing, change in body weight (Δweight) between scans correlated with change in LV end-diastolic volume (ΔLVEDV)  contains supplementary material, which is available to authorized users. There is an increased risk of cardiovascular (CV) mortality in chronic kidney disease (CKD), and end stage renal disease (ESRD) populations . This inCardiovascular Magnetic Resonance (CMR) with Late Gadolinium Enhancement (LGE) is an imaging biomarker used to assess myocardial fibrosis in many populations. Whilst gadolinium based contrast agents have previously been used to assess cardiac disease in HD patients  this is In this study we aim to assess the reproducibility and reliability of native T1 mapping in patients with ESRD on HD by assessing: i) the inter-study, inter-observer and intra-observer variability of native T1 times in HD patients at 3 Tesla (3 T); ii) the associations between changes in markers of fluid status and changes in native T1 times to assess the effect of fluid status on native T1 times; iii) the inter-centre reproducibility of native T1 values between two UK cardio-renal imaging centres, comparing analysis techniques of native T1 maps and native T1 values with ‘phantom’ analysis .Patients from centre 1 were recruited as a part of the CYCYLE-HD study (ISRCTN 11299707) . The stuTen patients underwent a repeat CMR scan within 2 weeks of their initial scan. Patients receive dialysis three times per week on either a Monday, Wednesday, Friday, or a Tuesday, Thursday, Saturday. This means that there is a two-day break between dialysis once a week, commonly referred to as ‘the long break’. Study patients were all scanned on a non-dialysis day within 24 h after their last dialysis and never during the long-break. The same CMR protocol was used for each scan (see below). We report the inter-study reproducibility of LV volumes, mass and of the mid-ventricular native T1 parametric mapping. Analysis of inter-study scans was conducted by a single, blinded, observer. Inter-observer variability of was conducted by 2 blinded observers on 10 native T1 maps independently from one another. Intra-observer variability was conducted by a single blinded observer.The inter-observer variability of native T1 map analysis techniques between 2 UK cardio-renal imaging centres was assessed. The CMR scanners, native T1 mapping sequences and analysis techniques of centre 1 and centre2 were different (see below). Ten basal and 10 mid-ventricular native T1 scans acquired at centre 1 were analysed by a blinded observer at centre 2, using the analysis technique of centre 2 and compared to the results of the analysis of the same scans analysed at centre 1. Conversely 10 basal and mid-ventricular native T1 scans acquired at centre 2 were analysed by a blinded observer at centre 1, using the analysis technique of centre 1 and compared to the results of the analysis of the same scans analysed at centre 2. We also undertook native T1 phantom analysis at both centres. Phantom analyses were undertaken at centre 1 and centre 2 as part of the international, multi-centre T1MES project . PhantomThe CMR protocols at centres 1 and 2 were pre-defined in the CYCLE-HD and CUDDLE studies respectively. Differences in scan parameters are due to local expertise in gaining the highest quality images possible with the fewest number of artefacts.0, temporal resolution <50 ms, with 30 phases per cardiac cycle, in-plane image resolution 1.1 x 1.5 mm to 1.3 x 1.7 mm.All patients were imaged on a 3 T CMR platform  using an 18-channel phased-array anterior coil. Patients were scanned on non-dialysis days, but not after the long-break. The CMR protocols for acquiring cine imaging and native T1 maps were as previously described . ElectroT1 imaging parameters included acquisition of basal and mid T1 maps in 2 LV short-axis slices using the modified look-locker inversion recovery (MOLLI) sequence. Images were acquired using free-breathing with motion correction (MOCO), ECG-gated single-shot MOLLI sequence , with 3 using a 16 channel phased-array anterior coil. As at centre 1 CMR imaging was performed on a non-dialysis day. Image acquisition was ECG-gated and as previously described . T1 imag42 . Image quality was assessed as being excellent, good, acceptable or poor. LV volumes and mass were quantified as previously described with epicardial and endocardial short axis cines at end- diastole and end-systole [All scans were analysed offline by a single blinded observer using the software package CMR-systole . The nat-systole . Using tAll scans were analysed offline by a single blinded observer using Siemens Argus Analysis software . The image analysis technique was as previously described . LV contStatistical analysis were undertaken using SPSS-22 software  and Graphpad Prism version 6.04 . Normality was assessed using the Shapiro–Wilk test, histograms, and Q–Q plots. Normally distributed data are expressed as mean ± standard deviation and non-normally distributed data are expressed as median (interquartile range). Interstudy and inter-observer variability for subjects undergoing test-retest scans were compared using paired t-tests, co-efficients of variation and the Bland-Altmann method . Inter-ct-test sample size calculation was undertaken for the native T1 test-rest study, using the native T1 values from a previous study by our group conducted on the same 3 T MRI scanner  [A paired Germany) . To deteP = 0.62 and mid T1 1282.6 ms ± 38.1 vs 1283.4 ± 39.3, P = 0.42). All scans were analysable and included in the analysis.The demographic data for all patients from both centres are shown in Table n = 4) or excellent (n = 16) and of sufficient quality for quantitative analysis. The inter-study reproducibility, including coefficients of variation (CoV), bias and limits of agreement for LV mass, LVEDV, LVESV and LVEF are shown in Table r = 0.682, P = 0.03), but no association was found between change in LV mass (ΔLVMass) and ΔLVEDV or Δweight   . Based on these results, to detect a 2.5% difference in native T1 values with 90% power would require 13 patients and to detect a 5% difference in native T1 values with 90% power would require 5 patients .Six out of 120 native T1 segments from mid-ventricular native T1 parametric maps were excluded from analysis due to artefact. The same segments were excluded from analysis by the two readers in the inter-observer analysis . The inter-study reproducibility, inter-observer and intra-observer variability of mid-ventricular native T1 values, including CoV, bias and limits of agreement for mid-LV native T1 values are shown in Table Twenty-five out of 240 native T1 segments were excluded from analysis due to artefact . The two readers agreed on the analysability of 220/240 segments reviewed (91.7%). The inter-centre variability of native T1 analysis techniques of basal and mid-ventricular native T1 values, including CoV, bias and limits of agreement are shown in Table Excellent agreement was seen for the phantom results obtained at both centres with no clinically relevant differences between scanners. Allowing for standard deviations, the phantom considered representative of a typical myocardial tissue T1 time, gave very similar T1 values at both sites . For the phantom blood pool T1 times obtained were again equivalent at each centre: .In this study we have shown, for the first time in patients with ESRD on HD, that the reproducibility of native T1 values are excellent. The reproducibility values for T1 mapping using the MOLLI sequence compare favourably with those previously reported. Previous CoVs for inter-study reproducibility have been between 1.5 and 8.4%, –16, 29 cWe have demonstrated that standardization of native T1 mapping analysis between centres is eminently possible. The agreement between the analysis techniques of centres is encouraging. Both techniques define segmental native T1 values for basal- and mid-ventricular slices as per the American Heart Association model , and that septal T1 values correlate with pre-dialysis high-sensitive troponin T  [r = 0.41, P = 0.002, r = 0.55, P < 0.001) and septal native T1 correlated with septal systolic strain  [In 2011, Sado et al outlined a framework for development of imaging techniques to measure myocardial fibrosis, to ensure the robustness of the techniques . They su= 0.027) . In addi< 0.001) .Following the framework outlined by Sado et al, histological confirmation of the relationship between myocardial fibrosis and native T1 mapping now appears to be the final step required before longitudinal and interventional studies can be undertaken to define whether native T1 mapping is able to: track progression of myocardial fibrosis over time; assess how baseline or changes in native T1 values relate to outcomes; whether interventions that attempt to modify/improve fibrosis are measurable by native T1 mapping; and whether this modification improves outcomes for patients. The excellent reproducibility of native T1 mapping makes it a biomarker with great potential for the measurement of myocardial fibrosis in HD patients. Based on the results we have presented, only small numbers of patients would be required to adequately power interventional clinical trials that seek to reduce myocardial fibrosis. Whilst historically LV mass has been the surrogate end-point for clinical trial work that sought to improve CV outcomes, a recent systematic review and meta-analysis has called into question whether interventions that improve LV mass actually improve outcomes for patients with CKD and ESRD . It shouNative T1 mapping is an extremely reproducible technique in HD patients. Native T1 times seem to be unaffected by the changes in fluid status to which HD patients are prone. Further work is required to determine whether native myocardial T1 is related to prognosis in ESRD and whether interventions that reduce T1 are associated with improved outcomes.


Editorial on the Research TopicNeuro-Development and Psychological Issues in Congenital Heart DefectsThe operative mortality in infants with congenital heart defects has dramatically decreased in the past few decades to less than 3% in all databases of Europe and North America. As a result, attention has been moved from the survival to the quality of life. Surviving children often experience neurodevelopmental deficits and behavioral, emotional, and social problems, which can have a profound impact on their quality of life. This Research Topic focused on recent studies conducted in this field, to predict, evaluate, and manage the neurodevelopmental and psychological outcomes after congenital heart surgery.Moon et al. studied 180 adolescents, analyzing the relationship between parental rearing behavior, resilience, and depressive symptoms. They demonstrated that parental rearing behaviors, such as emotional warmth, rejection, punishment, control, and overprotection have a significant influence on the resilience of the adolescents. They suggested that parenting attitudes, gender, age, and severity of the defects should be taken into consideration when developing intervention programs to increase the resilience and reduce the depression in these adolescents.Meentken et al. did an extensive review of post-traumatic stress, with a particular focus on stress related to medical interventions and treatment due to their underlying congenital heart defects, particularly for invasive interventions. The authors concluded that children with congenital heart defects present with an elevated risk of developing posttraumatic stress. Therefore, early screening of psychological problems and, if indicated, referral for psychological treatment should be made early on in this group of patients.In another study on children and adolescents with congenital heart defects, Pike et al. evaluated memory deficits in 80 adolescents and young adults with congenital heart defects, more than a decade following their last surgery in comparison to 76 healthy controls. Long after surgery, the group with congenital heart defects demonstrated significant verbal, attention, and working memory deficits over the control group. To enhance patient memory/self-care, the authors recommend to reduce anxiety, improve self-efficacy, and use of visual patient education material.Buratti et al. studied 184 children, adolescents, and their parents, where heart malformations were divided in mild, moderate, and severe. Irrespective of the severity of the cardiac malformation, a strong association was found between the parent’s ratings of cognitive problems and the children’s and adolescents’ results on intelligence (Wechsler) scales, with this association present for all ages.Helm et al. conducted a survey into transition in Germany in 1828 patients with congenital heart defects after they had turned 18 years of age. Their survey revealed that after age 18, many young adult patients had not been transferred to certified adult congenital heart defects providers and about 1/3 were not in continuous care at a specific adult congenital heart defects clinic/heart center. These observations regarding the adult certification were particularly disappointing and indicative of a large information gap and inadequate education in the current clinical practice.Kolaitis et al. performed an extensive literature review into parental mental health at the time of the diagnosis of congenital heart defect, following cardiac surgery, and at long-term, assessing the need for psychological care. Their review confirmed that parents of children with congenital heart defects, and especially the mothers, are at higher risk for a variety of mental health problems at all different time periods of their children’s illness.Hövels-Gürich identified that the factors influencing the neurodevelopment in infants undergoing cardiac surgery are not only related to the methods of cardiopulmonary bypass, procedure specific risk factors, and postoperative management but also patient specific risk factors, family and environmental factors.In a literature review, Ryberg et al. investigated 228 children who underwent either surgery or interventional cardiology procedure. Their research demonstrated that socioeconomic status of the families and the severity of diagnosis had a significant influence on the full scale IQ of the children.Kasmi et al. focused on neurodevelopment and psychiatric outcomes in a specific group of patients: those born with transposition of the great arteries. The authors conducted a detailed systematic review. They describe the results within a life-span perspective, putting particular emphasis on adolescent/young adult neuropsychological outcomes, describing potential mechanisms by which pediatric neurodevelopmental impairments can have negative influences into adulthood and also interventions to improve the clinical outcomes.Etnel et al. designed a pilot project developing an online, evidence-based information portal, with information on aortic and pulmonary valve disease, supported by both patients and physicians. If successful, this information portal will be further developed and expanded to include all common congenital heart defects, translated into other languages, and developing into a public information portal to serve patients’ relatives and the general public at large.In response to an increased need for patient information congenital heart defects, The studies and reviews collected in this Research Topic demonstrate that the success obtained by substantially reducing the mortality in the repair of congenital heart defects has not been followed by corresponding improvement in the quality of life.While surgery does provide patients with a better life style related to their physical health, with less cyanosis, heart failure, and better exercise tolerance, much progress is still needed to improve the neurodevelopment outcomes and psychological health of these patients. We are now beginning a new era of research and clinical efforts to prevent and reduce the negative impact of congenital heart defects. Improved psychosocial interventions that caregivers, social workers, and behavior health providers can deliver to support patients and their families are urgently needed.AC and EU co-wrote this manuscript.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.


Patients with cardiac amyloidosis are at increased AV-block and syncope risk. Therefore, a prophylactic pacemaker is often implanted. However, this case illustrates that other mechanisms should be ruled out prior to pacemaker implantation. The patient studied had mitral valve thickening without increased left ventricular outflow track (LVOT) velocity. However, bicycle exercise-stress test with simultaneous echocardiography revealed a stepwise decrease in blood pressure, a substantial increase in the LVOT velocity, and severe systolic anterior motion of the mitral valve. The patients' symptoms were likely explained by these findings. Therefore, a comprehensive clinical evaluation is warranted prior to pacemaker implantation in cardiac amyloidosis patients. A 71-year-old previous healthy man was referred to cardiac evaluation due to symptoms of dyspnea, orthostatic dizziness, and episodes of postural related syncope during a period of 2 months.λ-light chains and negative for transthyretin, amyloid A, and κ-light chains.Electrocardiogram revealed low-voltage limb leads and first degree of AV-block . EchocarPacemaker implantation was considered due to the previous syncopes and the findings of first degree of AV-block. However, we decided to evaluate the hemodynamics of the patient during a semisupine bicycle exercise-stress test with simultaneous echocardiography. At rest, blood pressure (BP) was 108/68 mmHg and heart rate (HR) was 90 beats/min. At 10 Watts BP was 98/61 mmHg, HR was 94 beats/min, and LVOT velocity was still normal at 1.5 m/s. At 30 Watts BP declined to 88/51 mmHg, HR was 98 beats/min, and LVOT velocity was between 2.0 and 3.5 m/s with a shark fin pattern. At peak exercise (40 Watts), BP was 74/45 mmHg and HR 106 beats/min. Severe SAM was noted at this point and the patients felt dizziness and dyspnea. The LVOT velocity was between 2.5 and 3.6 m/s .The present case illustrates that mitral leaflet SAM should be suspected in CA patients with dizziness and syncopes, especially if echocardiography shows involvement of both the myocardium and mitral valve. This is important as CA patients with syncopes traditionally receive prophylactic pacemaker implantation. Previous case reports have demonstrated obstruction of the left ventricular outflow tract in CA patients –3. The uOptimal treatment of left ventricular outflow tract obstruction in CA patients is difficult. The risk of surgical myectomy or mitral valve plasty is considered to be significantly increased . The effIn conclusion, mitral leaflet SAM should be ruled out prior to pacemaker implantation in CA patients. Furthermore, exercise-stress echocardiography may prove benefit in the clinical surveillance of CA patients.


Cardiovascular magnetic resonance (CMR) imaging has long been used to calculate the ejection fraction (EF) of the left ventricle (LV) and more recently to calculate the ventricular-vascular-coupling (VVC) ratio, both entirely measured within the LV. Here we seek to demonstrate the role of blood transmission efficiency measure within the aorta.To establish the nature of the linkage between aortic vascular ejection efficiency (VEE) and LV EF and VVC which may prove useful for predicting future LVEF decline.Vascular ejection efficiency (VEE) is proportional to the dimensionless ratio of aortic diameter to wavelength of the transmitted blood pulse. The wavelength of ejected blood is proportional to blood wave velocity divided by blood wave frequency measured using phase velocity mapping (PVM) applied to the ascending aorta. Left ventricular function and aortic PVM data were retrospectively obtained in 118 patients who underwent CMR scanning as a clinical routine. The LV end-diastolic and end-systolic volumes were measured using manually drawn contours for a contiguous stack of LV slices. The aortic area was measured from the PVM images along with the average velocity, taken as a measure of blood wave velocity (not to be confused with the more common pulse wave velocity), the end-systolic time was taken as the pulse length and aortic area instead of diameter to yield the VEE index:VEE = Aortic Area × End systolic time / Average blood velocityThe VEE was calculated and plotted against the ventricular measures of EF and VVC.In the plots of EF vs. VEE patients stratified into three regions, Figure We show that vascular ejection efficiency (VEE) measured in the aorta relates to LV EF measured in the ventricle via a series of power relationships, which accommodates the precipitous decline in EF at the lower levels of VEE. VEE may permit more effective risk-stratification and early detection for patients who are near an abrupt decline in LV systolic function. To date, predictive modeling for predicting precipitous declines in cardiac function is not in existence.