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Changes in overall ventricular myocardial architecture in the setting of a porcine animal model of right ventricular dilation
© The Author(s). 2017
Received: 6 April 2017
Accepted: 18 October 2017
Published: 27 November 2017
Chronic pulmonary regurgitation often leads to myocardial dysfunction and heart failure. It is not fully known why secondary hypertrophy cannot fully protect against the increase in wall stress brought about by the increased end-diastolic volume in ventricular dilation. It has been assumed that mural architecture is not deranged in this situation, but we hypothesised that there might be a change in the pattern of orientation of the aggregations of cardiomyocytes, which would contribute to contractile impairment.
We created pulmonary valvular regurgitation by open chest, surgical suturing of its leaflets in seven piglets, performing sham operations in seven control animals. Using cardiovascular magnetic resonance imaging after 12 weeks of recovery, we demonstrated significantly increased right ventricular volumes in the test group. After sacrifice, diffusion tensor imaging of their hearts permitted measurement of the orientation of the cardiomyocytes.
The helical angles in the right ventricle approached a more circumferential orientation in the setting of right ventricular RV dilation (p = 0.007), with an increased proportion of surface-parallel cardiomyocytes. In contrast, this proportion decreased in the left ventricle. Also in the left ventricle a higher proportion of E3 angles with a value around zero was found, and conversely a lower proportion of angles was found with a numerical higher value. In the dilated right ventricle the proportion of E3 angles around −90° is increased, while the proportion around 90° is decreased.
Contrary to traditional views, there is a change in the orientation of both the left ventricular and right ventricular cardiomyocytes subsequent to right ventricular dilation. This will change their direction of contraction and hinder the achievement of normalisation of cardiomyocytic strain, affecting overall contractility. We suggest that the aetiology of the cardiac failure induced by right vetricular dilation may be partly explained by morphological changes in the myocardium itself.
Right ventricular dilation is often caused by pulmonary valve regurgitation, which is predominantly seen in congenital heart disease following balloon dilation of critical pulmonary stenosis, or perforation of valvar pulmonary atresia . The most important, and well-described, clinical context for pulmonary regurgitation, however, is in patients with repaired tetralogy of Fallot, the most common cyanotic congenital heart disease .
We have previously investigated the alterations in the right ventricular myocardial architecture in two animal models of increased right ventricular pressure overload [6, 20]. We were able to show that the myocardial architecture does change as a consequence of increased afterload brought upon by persistent pulmonary hypertension in the newborn . Since dilation arises from a different pathogenetic mechanism as compared to hypertophy, this raised the question as to whether such morphological changes are also to be found in the setting of right ventricular dilation. For this purpose, we have introduced a porcine model of right ventricular dilation  and heart failure . In this study, we aimed to compare the orientations of the aggregated cardiomyocytes in the normal and dilated right ventricular myocardium.
Fourteen female 5 kg Danish landrace pigs were studied. The animals were randomised into two groups of equal size (N = 7). Each animal was pre-anaesthetised with midazolam (0.5 mg/kg) and azaparone (0.5 mg/kg). Intravenous access was established through an ear vein. The pre-anaesthesia was supplemented intravenously with propofol (3 mg/kg) to allow endotracheal intubation and coupling to a ventilator. Anaesthesia was maintained by 3% inhalational sevoflurane, and analgesia was achieved with fentanyl (25 μg/kg/h) before surgery. Postoperative analgesia was achieved with flunixine (25 mg). Antibiotics consisted of penicillin, given as a dose of 100,000 IU before surgery. Neuromuscular block was obtained using pancuronium at a dose of 0.2 mg/kg at the beginning of surgery. In the group destined for right ventricular dilation, having obtained assess through a left lateral thoracotomy, we exposed the pulmonary trunk. We placed 4 to 6 sutures through its wall to secure the valvar leaflets to the inside of the root, thus creating the substrate for pulmonary valve regurgitation. Having evacuated the pneumothorax, we closed the incision in three layers and aroused the piglet, confirming the success of the procedure by postoperative echocardiography.
After 12 weeks, we again anaesthetised the animals using the same protocol as outlined above. After conventional cardiovascular magnetic resonance scanning the animals were brought to the experimental operating theatre, where we removed the heart through a median sternotomy, having administered 10,000 IU of heparin. Subsequent to excision, we infused 1 l of potassium rich cold cardioplegic solution (Kardioplex; H/S Apoteket, Copenhagen, Denmark) directly through the coronary arterial orifices at a pressure of approximately 100 mmHg at the point of the tip of the catheter. In order to maintain the normal end-diastolic state, we then injected a thin slurry of water-based MRI compatible polymer into the ventricles via the orifices of the atrioventricular valves. To avoid excess ventricular dilation, we injected the polymer until it escaped smoothly via the pulmonary and aortic valvar orifices. Having given approximately 15 min for the polymer to harden, the hearts were perfused with formalin at pH 7.4 using the same method as with the cardioplegic solution outlined above. The hearts were then stored submerged in formalin for a minimum of 24 h, perfused with phosphate buffered solution, also at pH 7.4, and stored at 4–5 °C until scanning.
Cardiovascular magnetic resonance imaging
Cardiovascular magnetic resonance was performed with a 3.0 T system (Siemens Skyra; Siemens Healthcare, Erlangen, Germany). For the initial scans, the piglets were again anaesthetised, mechanically ventilated, and placed on the scanner bed in supine position. The orientation of the left ventricular long axis was determined using scout images. A stack of 12 contiguous short-axis slices encompassing the ventricles from base to apex was acquired during end-expiratory apnea using a retrospective, electrocardiogram -triggered balanced-steady-state-free-precession breath-hold cine sequence. Imaging parameters were set as follows: repetition time = 3.8 ms, echo time = 1.67 ms, flip angle = 43°, acquisition matrix = 336 × 235, field of view = 340 × 273 mm2, spatial in-plane resolution = 1.01 × 1.45 mm2, slice thickness = 6 mm, number of heart phases = 40.
For measuring cardiac output, we used a phase contrast flow sequence. The measurement slice was positioned across the pulmonary trunk at the level of the sinotubular junction, using a sequence triggered by the electrocardiogram, but running during free breathing. The sequence parameters were set as follows: field of view = 200 × 200 mm2, acquisition matrix = 128 × 128, in-plane resolution = 1.56 × 1.56 mm2, slice thickness = 3.2 mm, repetition time = 15.6 ms, echo time = 4.63 ms, flip angle = 15°, flow encoding velocity = 200 cm/s. The number of cardiac frames was set to 86 and the overall scan time was 3 min.
Diffusion tensor cardiovascular magnetic resonance imaging
For the purposes of scanning the excised hearts, the scans were performed with an Agilent 9.4 T preclinical MRI system (Agilent, Santa Clara, CA), equipped with 400 mT gradients and vnmrJ 4.0 software. The hearts were placed with the left ventricular long-axis aligned parallel to the axis of the main magnetic field. Room temperature was maintained constant at 22.0 ± 1.5 °C and humidity at 50 ± 10%. Measurements were performed using a standard multi-slice 2D spin-echo sequence with an in-plane voxel resolution of 400 × 400 μm2. Repetition time: 7000 ms, echo time: 30 ms. Using 30 isotropically distributed diffusion directions  with the b-factor equal to 1000 s/mm2 and one with b = 0 s/mm2, 125 slices with 800 μm slice thickness were acquired. Scan time was approximately 15 h for each heart.
The left and right ventricular myocardial masses were subdivided into 23 zones as previously described . Using the in-vivo cardiovascular magnetic resonance data, mean left ventricular wall thickness was measured by four measurements at the level of the papillary muscles in zones 7 and 10, between zones 8 and 9, and between zones 11 and 12. The left ventricular anterior to posterior ventricular diameter (AP), and septal to lateral free wall dimension (SL), were also measured, permitting calculation of the SL/AP ratio as a surrogate measure of septal deviation. We were unable to measure right ventricular mural thickness in-vivo within an acceptable error margin due to insufficient spatial resolution. Left ventricular volume through the cardiac cycle was assessed and cardiac index was calculated. Likewise, we measured right ventricular volume along with its dimensions in terms of length and distance from the septum to the free wall. The pulmonary regurgitation volume was estimated using the acquired flow data. All image analyses of in-vivo data were done using the freely available software Segment version 2.0 R4942 (http://segment.heiberg.se) . Assessment of the ventricular mural diastolic thicknesses in diastole ex-vivo was achieved using the diffusion-weighted images, taking the distance between the most epicardial and the most endocardial voxel in the centre of each zone.
Measurements of myocardial architecture
Diffusion tensor imaging data were visualised using custom made software [6, 13]. The three eigenvectors of each voxel within the myocardium were calculated. The vector data was subsequently imported in Mathematica 9 (Wolfram Research, Inc., Champaign, Illinois, USA (2012)). The datasets were rotated aligning the left ventricular long axis with the z-axis of the overall coordinate system. Three short axis slices of interest were selected, one from the middle of the basal third of the heart, one from the equatorial third being the level of the papilary muscles and lastly one from the middle of the apical third of the heart. Papillary muscles, interventricular hinge points and the apical vortex were excluded by omitting analysis of zones 1, 4, 10, 12 and 17. Conversely, endocardial trabeculations were included in the analyses because they play an important role in the myocardial contraction. We are aware that this inclusion can introduce partial volume effects especially in the transition zone between compact myocardium and trabeculations. We consider this to have only minor impact on our results owing to the high resolution of our data.
We assessed the overall three-dimensional mural architecture using a custom-made FACT tractography algorithm [13, 25]. We selected a number of voxels, and then permitted the software to track through the primary eigenvectors, using a fractional anisotropy threshold of 0.15 and an inner product of 0.75 as previously described [26, 27]. By colour-coding the tracks, we were able to distinguish up to six different pathways. Since the total number of voxels is enormous, we selected predetermined myocardial locations for tractography. These were the right vetricular free wall at the rightmost, posterior, and the anterior aspects at the level of the left ventricular papillary muscles, and the septal right ventricular myocardium at the same level.
Initially normality was tested in all variables on individual subject level using quantile plots, histograms and Shapiro-Wilk test. Anatomical and haemodynamic data were compared between groups using Wilcoxon ranksum test. Differences between the groups of the distributions of each angle type were tested using two-sample Kolmogorov-Smirnov test. Helical and intrusion angles were binned for each zone relative to myocardial level in 10% intervals where the overall median angle for each bin was calculated and compared between groups using Mann-Whitney U-test. Data are reported as medians with interquartile range in parentheses. Note that E3-angle data were heterogeneously distributed throughout the myocardium, thus angle differences based on myocardial level was not tested. All statistical tests presumed a significance level of 5%. Stata Statistical Software, release 11 (StataCorp LP, College Station, Texas, USA) and Mathematica 9 (Wolfram Research, Inc.) was used for statistical analyses.
Cardiovascular magnetic resonance imaging
Cardiovascular MRI assessment
Number of animals
Body surface area (m2)
Heart rate (bpm)
Left ventricular indices
Stroke volume (ml/m2)
Ejection fraction (%)
Cardiac index (l/min/m2)
LV SL/AP ratio, systole
LV SL/AP ratio, diastole
In-vivo wall thickness, systole (mm)
In-vivo wall thickness, diastole (mm)
Ex-vivo wall thickness, diastole (mm)
Right ventricular indices
RV ejection fraction (%)
RV regurgitation volume (ml/m2)
RV regurgitation fraction (%)
Ventricular length, systole (mm)
Ventricular length, diastole (mm)
Septum-lateral distance, systole (mm)
Septum-lateral distance, diastole (mm)
Ex-vivo wall thickness, diastole (mm)
Diffusion tensor imaging
Helical Angulations of Cardiomyocytes
The intrusional angles showed the most obvious changes in the right ventricle as seen in Fig. 3, where the proportion of surface parallel cardiomyocytes increased. Statistical testing on myocardial level only revealed significant differences in the septum by a decrease in intrusional angle in the right ventricular sub-endocardium of approximately 5° (p = 0.04), see Fig. 4.
Figure 3 also shows that significant differences for the E3 angles were found in both ventricles, with a slightly higher proportion of angles for the left ventricle with a value around zero, and conversely a lower proportion of angles with a numerically higher value. In the dilated right ventricle the proportion of E3 angles around −90° is more markedly increased, while the proportion around 90° is decreased. No differences were found for measurements taken in the ventricular septum. As shown in Fig. 5, E3 angles were distributed very heterogeneously within the myocardium. It was not justifiable, therefore, to plot them as a function of myocardial depth and hence the difference in angle distribution could not be attributed to a specific myocardial region. Because of this, we excluded E3 plots from Fig. 4.
We found an increase in the amount of circumferentially oriented cardiomyocytes in the right ventricle as was also found in the study of Sanchez-Quintana and co-workers achieved by dissecting human hearts with tetralogy of Fallot . The physiological mechanisms of the myocardial remodelling observed in the presented model and in tetralogy of Fallot, however, are quite different. In this study, we have investigated a volume overload model, whereas tetralogy of Fallot is a pressure overload disease. Although the proportion of circumferentially oriented cardiomyocytes increases in the dilation model, the etiology is quite different from that observed in the setting of tetralogy. It could be argued that the increase of circumferentially oriented myocytes in tetralogy is a compensatory mechanism as part of myocardial hypertrophy, whereas in dilation the increase in circumferential myocytes is merely a disadvantageous mechanical consequence of expanding the cavity of the ventricle. Realignment of the cardiomyocytes must also lead to alterations in how the contraction of the myocytes affects the ventricle. Mathematical models as presented by Sallin and associates and ourselves have argued that the presence of a helical angle is mandatory in order to produce an ejection fraction within physiologically normal range [40, 41]. Moreover, a recent study in humans with situs inversus totalis by Khalique and co-workers found an altered helical angle pattern in the left ventricle leading to reduced torsion . Even though all three of these works only study the left ventricle, it is highly likely that the myocardial rearrangement in the dilated right ventricle towards a helical angle of zero degrees is not beneficial for right ventricular cardiodynamics. It could very well be part of the explanation of the heart failure that will eventually result from ventricular dilation .
Our study has also shown that left ventricular myocardial remodelling is brought about by pulmonary regurgitation, as evidenced by the observed changes in the distribution of the E3 angles. The proportion of angles with a numerically low value around zero increases concomitant with right ventricular dilation. This phenomenon has been described previously, since it is the same pattern as seen when the heart approaches the systolic contractional state . The systolic-like configuration of the E3 angles in the present study, however, is not associated with the anticipated mural thickening. The helical angles in the left, and especially the right, ventricle furthermore have a more diastolic configuration, with values closer to zero. Hence, there is a mismatch between the state of contraction and the configuration of the cardiomyocytes. This is in keeping with our findings in our sheep model of right ventricular pressure overload in persistent pulmonary hypertension of the newborn . In this setting, we found the reverse situation, with the cardiomyocytes configured in a more diastolic state in spite of myocardial hypertrophy. In both studies, therefore, we describe types of mismatch between contraction state and myocyte architecture that could potentially aid in the explanation of heart failure in myocardial remodelling. There is great difference in literature on how to quantify the orientation of aggregations of cardiomyocytes. Some quantify them as absolute values , while others, such as ourselves consider the orientations with a sign. Our results underline why this is important. When contemplating Fig. 8 it is clear that positive and negative E3-angles are not equally distributed and, moreover, changes in the distributions caused by right ventricular dilation do not affect positive and negative angles equally. Differentiation between positive and negative angles is, therefore, indeed important although the functional interpretation of the differences between positive and negative E3 angles is far from clarified. In addition, we cannot unequivocally answer the question as to why right ventricular volume overload, in time, causes heart failure. Heart failure is well recognised to be a multifaceted disease, with a complex aetiology which probably also varies depending on the cause of failure . We have now seen several cases of myocardial remodelling in the development of heart failure, but questions regarding the threshold relative to clinical heart failure, and the reversibility of the myocardial remodelling, have never been investigated. If this proved possible, then the specific role of remodelling in heart failure could potentially be more clearly elucidated.
Our present study indicates that remodelling as seen relative to mural architecture may play a part in the pathophysiology of heart failure in right ventricular dilation. This remodelling may simply come to pass by mechanical effects on the myocardium brought upon by pulmonary regurgitation. A mismatch is found between the alignment of the aggregated cardiomyocytes and the cardiac contractional state indicating that remodelling might not fully achieve the benefit intended.
The authors are grateful for the valuable help provided by Camilla Omann Christensen for MRI data analyses. Likewise, we thank Dr. Robert S. Stephenson for his much appreciated scientific comments on the manuscript.
Ethical approval and consent to participate
The surgical procedures were conducted after approval from the Danish Inspectorate of Animal Experimentation, with the guidelines from this institution complying with “NIH publication No. 86–23”, regarding principles of laboratory animal care (revised 1985).
This study was made possible owing to grants from the Danish Childen’s Heart Foundation, The Arvid Nilsson Foundation and Aarhus University.
Availability of data and materials
The data sets during and/or analysed during the current study available from the corresponding author on reasonable request.
PA and MS designed the study. PA and CI performed the surgical interventions. PA, CI and SR performed the in-vivo MRI assessments. PA and CL performed the diffusion tensor imaging sequences. JRF designed the analysis software. PA wrote the initial draft of the final paper. MS, MP, JBP, RHA and VH edited the draft and provided important scientific discussion for the finalisation of the manuscript. All authors read and approved the final manuscript.
Consent for publication
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