Abstract
Introduction:
Annular reduction with prosthetic rings represents current surgical treatment of functional tricuspid regurgitation (FTR). However, alterations of annular geometry and dynamics associated with FTR are not well characterized.
Methods:
FTR was induced in 29 adult sheep with either eight weeks of pulmonary artery banding (PAB, n=15) or 3 weeks of tachycardia induced cardiomyopathy (TIC, n=14). Eight healthy sheep served as controls (CTL). At terminal procedure, all animals underwent sternotomy, epicardial echocardiography, and implantation of sonomicrometry crystals on the tricuspid annulus (TA) and RV free wall while on cardiopulmonary bypass. Simultaneous hemodynamic, sonomicrometry, and echocardiographic data were acquired after weaning from CPB and stabilization. Annular geometry and dynamics were calculated from 3D crystal coordinates.
Results:
Mean FTR grade (0–4) was 3.2±1.2 and 3.2±0.5 for PAB and TIC, respectively with both models of FTR associated with similar degree of RV dysfunction (RVFAC 38±7% and 37±9% for PAB and TIC, respectively). LV ejection fraction was significantly reduced in TIC versus baseline (33±9%, vs 58±4%, p=0.0001). TA area was 651±109, 881±242, and 995±232 mm2 for CTL, FTR, and TIC, respectively (p=0.006) with TA area contraction of 16.6±4.2, 11.5±8.0, and 6.0±4.0%, respectively (p=0.003). Septal annulus increased from 33.8±3.1 to 39.7±6.4 and 43.1±3.2 mm for CTL, PAB, and TIC, respectively (p<0.0001).
Conclusion:
Ovine FTR was associated with annular dilation and reduced annular area contraction. Significant dilation of septal annulus was observed in both models of FTR. As tricuspid rings do not completely stabilize the septal annulus, continued remodeling may contribute to recurrent FTR after repair.
Keywords: tricuspid valve, functional tricuspid regurgitation, valve repair
Graphical Abstract
Introduction
Functional tricuspid regurgitation is clinically associated with tricuspid annular dilation and right ventricular dysfunction and remodeling, yet the pathophysiology of valve insufficiency is incompletely understood.1 Repair with prosthetic ring annuloplasty represents the contemporary approach to functional TR to reduce and stabilize the anterior and posterior portions of the tricuspid annulus which are believed to dilate during evolution of FTR.2 This strategy, however, is associated with high rates of residual and recurrent insufficiency in the setting of severe FTR.3,4 Some investigators have suggested isolated ring annuloplasty is insufficient to treat severe FTR as associated ventricular and subvalvular geometric perturbations are already advanced1, but the detailed three dimensional geometry of the tricuspid annulus in severe FTR has not been well described. A recent clinical study demonstrated that all segments of the tricuspid annulus including the septal annulus enlarge during progression of FTR5. Therefore currently available annular prostheses6 may not adequately support the dilated annulus as all leave a portion of the septal annulus unsupported. It is feasible that continued dilation of this segment of the annulus in severe FTR may contribute to residual and recurrent insufficiency after repair. As such more detailed knowledge of tricuspid annular dynamics and geometry in the setting of severe FTR may lead to more rational prosthesis design and improved reparative techniques. With this goal in mind, we set out to investigate tricuspid annular geometry and dynamics in two chronic ovine models of right ventricular dysfunction and clinically significant FTR.
Methods
All animals received humane care in compliance with the Principles of Laboratory Animal Care. The study protocols were approved by Calvin University Institutional Animal Care and Use Committee protocol number 2018–438 and Michigan State University Institutional Animal Care and Use Committee protocol number 2020–35 approved on 7/27/2020.
Surgical preparation
A total of 47 adult healthy Dorset male sheep (age 9–12 months) were used for the study. We chose to use the ovine model as sheep are sturdy experimental animals that tolerate cardiac procedures well and are docile and easy to take care of post-operatively. Their body size and hearts are of human size facilitating clinical procedures and imaging. Functional tricuspid regurgitation (FTR) was induced in two groups of animals either through pulmonary artery banding (PAB, n=20) or tachycardia induced cardiomyopathy (TIC, n=19), and remaining sheep served as controls (CTL, n=8). Experimental animals underwent the respective procedure to induce FTR and subsequent terminal surgery while control animal underwent terminal surgery only.
Tachycardia Induced Cardiomyopathy (TIC)
The surgical protocol for TIC has been described in detail previously7 and will be presented here in abbreviated form. An external right jugular intravenous (IV) catheter was placed under local anesthesia with 1% lidocaine and subsequently animals were anesthetized with propofol (2–5 mg/kg IV), intubated, and mechanically ventilated. General anesthesia was maintained with inhalational isoflurane (1%−2.5%) and fentanyl (5–20 mg/kg/ minute). A sterile left mini-thoracotomy through the 6th intercoastal space was used to suture a monopolar pacing lead onto the lateral LV wall which was exteriorized to a pacemaker (Consulta CRT-P; Medtronic, Minneapolis, Minn) placed in the subcutaneous pocket near the spine. Control epicardial echocardiography was performed to assess biventricular function and valvular competence. The surgical incision was then approximated in standard fashion, and intercostal nerves in the region were infiltrated with 0.25% bupivacaine. After a 5-day recovery period, high-rate pacing protocol was initiated as described previously.8 Animals were paced for a mean of 22±6 days at a rate of 200 to 240 bpm until LV dysfunction (LV ejection fraction<30%) was seen on surveillance transthoracic echocardiography. Furosemide was used to treat symptoms of heart failure based on clinical examination. Subsequently, the pacer was turned off for 24 hours, and the animals were returned to the operating room for the terminal study.
Pulmonary Artery Banding (PAB)
The same anesthetic protocol as described above was used for the pulmonary artery banding procedure. A limited sterile left thoracotomy was made through the 4th intercoastal space, and epicardial echocardiography was performed to assess biventricular function and valvular competence. The internal mammary artery and main pulmonary artery were cannulated for simultaneous systemic and pulmonary pressure monitoring. An umbilical tape was used to encircle the main pulmonary artery and progressively tightened down with successive clip approximations until development of systemic blood pressure instability at which time the last clip was removed.9 Proximal pulmonary artery pressure after the removal of last clip was then recorded. The thoracotomy was subsequently closed, and the animals were extubated and monitored for 8 weeks with intermittent treatment with furosemide for evolving heart failure symptoms. Thoracentesis was performed occasionally when significant pleural fluid was diagnosed on surveillance echocardiography. After eight weeks, the animals were returned to the operating room for the terminal procedure.
Terminal Procedure
All experimental and control animals underwent the terminal procedure for sonomicrometry crystal implantation. After induction of anesthesia as described above, a 4Fr vascular access sheath was introduced through left carotid artery for arterial blood pressure measurements. Animals were fully heparinized, and the right carotid artery and right internal jugular vein were exposed in preparation for cardiopulmonary bypass (CPB). The operative procedure was performed through a sternotomy and the heart was exposed in a pericardial cradle. Epicardial echocardiography was repeated to assess biventricular function and valvular competence. A multi-stage 21F venous cannula was placed via the right jugular vein and advanced to the inferior vena cava, and arterial access was achieved using a 17F carotid artery cannula. While on cardiopulmonary bypass and with the heart beating, both cava were snared, and the right atrium opened. Six (2mm) sonomicrometry crystals (Sonometrics Corporation, London, Ontario, Canada) were implanted around the tricuspid annulus with one crystal at each commissure and one equidistant between the commissures (Figure 1). Thirteen crystals were implanted on the right ventricular epicardium along three equators of the right ventricular free wall with additional crystal at the right ventricular apex. Pressure transducers (PA4.5-X6; Konigsberg Instruments, Inc.) were placed in the right and left ventricle through the apex and in the right atrium. An ECG electrode connected to the sonomicrometry system was sutured to the right ventricular free wall. The animal was weaned from cardiopulmonary bypass and allowed to stabilize for 30 minutes to achieve steady state hemodynamics. Every animal received lidocaine IV drip (0.03mg/kg/min) to prevent ventricular ectopy. All animals were studied under open-chest experimental conditions and simultaneous hemodynamic and sonomicrometry data were acquired. At the conclusion of the experiment, the animals were euthanized by administering sodium pentothal (100mg/kg IV). The heart was excised, and proper placement of annular and ventricular crystals was confirmed.
Figure 1.
Schematic representation of the right ventricle with implanted sonomicrometry crystals (orange spheres) around the tricuspid annulus and on the right ventricular epicardium. Crystals #1–2-3 correspond to the anterior annulus, #3–4-5 to the posterior annulus, and #5–6-1 to the septal annulus.
Data Acquisition
Epicardial echocardiography to evaluate biventricular function and valvular insufficiency was performed with a 1.5- to 3.6-Mhz transducer and Vivid S6 ultrasound machine (GE Healthcare, Chicago, Ill). The degree of valvular insufficiency was assessed using American Society of Echocardiography criteria. The grading included comprehensive evaluation of color flow and continuous-wave Doppler. Tricuspid regurgitation was graded accordingly and categorized by an experienced echo sonographer (JB) as none or trace (0), mild (+1), moderate (+2), or moderately severe (+3) or severe (+4).
All sonomicrometry data were acquired using a Sonometrics Digital Ultrasonic Measurement System DS3 (Sonometrics Corporation, London, Ontario, Canada) as previously described.10 Data were acquired at 128Hz with simultaneous LVP, RVP, CVP and ECG recordings. Data from three consecutive cardiac cycles during normal sinus rhythm were averaged for each animal. All sonomicrometry recordings were analyzed with custom Matlab (Natick, MA) code. End-diastole was defined as the time of the beginning of positive deflection in ECG voltage (R wave) while end-systole (ES) was determined as the time of maximum negative dp/dt of left ventricular pressure.
Data analysis
Right ventricle volume was calculated using convex hull method based on epicardial and annular crystal coordinates. Annular centroid of all annular crystals was calculated and was subsequently used for transformation and rotation of point clouds with centroid as an origin and normal vector along with +z direction. A spline curve was fit along those six points to replicate the annulus. Triangular areas formed by those sequenced points and the centroid were all added to calculate tricuspid annular area. Similarly, perimeter was measured using the distance between the adjacent points along the spline. Tricuspid annular anterior-posterior diameter was calculated as the distance between annular crystals #1 and # 4 and septal-lateral diameters as distance between crystal #6 and #2 (Figure 1). Additionally, an ellipse was fit through the annular crystals using MATLAB program to obtain eccentricity (e), which defines the circularity of annulus (e=0 for a perfectly circular annulus while e> 0 for an ellipse). Green-Lagrange Strains were calculated for tricuspid annulus throughout the cardiac cycle with strain at maximal diastolic annular size as the reference configuration. Inhouse MATLAB calculations were performed to project mean values on to average annular configuration (spatial data) and VTK files were generated. These files were later imported to ParaView 5.0.0 (Kitware Inc, Open-source software, Sandia National Laboratories, Los Alamos National Laboratories) for temporal (end-isovolumetric contraction [EIVC], end-isovolumetric relaxation [EIVR], end-systole [ES]) visualization of strains for CTL, PAB, and TIC annulus.
All the data are presented as a mean with standard deviation, and measured parameters were compared between CTL, PAB, and TIC using ANOVA with Bonferroni correction and a p-value <0.05 considered significant.
Results
With pulmonary artery banding, mean pulmonary artery pressure in the PAB animals increased from 15±2 mmHg to 36±5 mmHg (p=0.0001). Three PAB animals died during the banding procedure one each from stroke, pulmonary artery hemorrhage, and acute right heart failure. Seventeen surviving animals had echocardiographic assessment after 8 weeks of follow-up which revealed that eleven animals developed severe TR, four developed moderate insufficiency, and two did not develop significant TR and were excluded for final study number of 15 PAB animals. In the TIC group, three animals died during the pacing protocol and follow-up echocardiography in remaining sixteen demonstrated severe TR in 6 animals, moderate-severe in 4, moderate in 5, and one animal without significant TR which was excluded. One TIC animal was excluded because of poor sonomicrometry data quality yielding final study number of 14 TIC animals. Hemodynamic and echocardiographic parameters before and after induction of FTR in PAB and TIC animals are demonstrated in Table 1. Both models of FTR were associated with similar degree of RV dysfunction, annular dilatation, and level of tricuspid insufficiency. As may be expected, TIC resulted in significant concurrent LV dysfunction and functional mitral regurgitation that was not observed in PAB. Hemodynamic parameters of all animal groups at the time of data collection during the terminal study are summarized in Table 2. Experimental animals had higher heart rates, but systolic blood pressure was not different between CTL, PAB, and TIC. PAB was associated with higher peak RV systolic pressure while higher central venous pressure was seen with TIC. Right ventricular end-diastolic volume calculated based on annular and free wall crystals was 126±13, 176±32, and 135±26 ml for CTL, PAB, and TIC, respectively. (p<0.001). Sonomicrometry derived measurements of annular dynamics and geometry are shown in Table 3. Significant annular area and diameter increase versus CTL was seen in both PAB and TIC while greatest reduction in annular area and perimeter contraction during the cardiac cycle was observed with TIC. Annular area at end-systole increased approximately 36% in PAB and 52% in TIC relative to control animals. Regionally, the posterior annulus enlarged little at end-systole with PAB and TIC while the anterior annulus increased by 13% and 24% with PAB and TIC, respectively. Surprisingly, the septal segment was 17% longer in PAB and 28% longer in TIC. As the TIC animals had significantly lower body weights, septal segment length to weight ratio was used for a more direct comparison. Septal segment length-to-weight ratio was 0.5± 0.1, 0.6±0.1 and 0.8±0.1 mm/kg for CTL, PAB, and TIC, respectively (p<0.001 by ANOVA). In this analysis, the septal segment was significantly longer in TIC versus PAB animals (p<0.05). Overall, the septal annulus underwent greatest dilation in both PAB and TIC while the anterior annulus had the greatest reduction in contractile function. Annular area and perimeter throughout the cardiac cycle are shown in Figure 2 with annular diameters and eccentricity summarized in Supplemental Figure 1. Anterior, posterior, and septal annular segment lengths during the cardiac cycle are depicted in Figure 3. Two dimensional reconstructions of the tricuspid annulus with regional strain maps relative to maximal diastolic annular area in CTL, PAB, and TIC are shown in Figure 4. Negative annular strain (contraction) was observed already at end-diastole indicative of pre-systolic annular contraction. Anterior portion of the annulus appeared most dynamic with reduced strain with PAB and TIC. These reconstructions also illustrate the enlargement and circularization of the annulus. Three-dimensional shape of the tricuspid annulus was determined as the deviation of each annular crystal from the annular plane determined by the 3D coordinates of all annular crystals. These data for all studied animals are schematically summarized in Supplemental Figure 2 which revealed that the three-dimensional shape of the TA did not change significantly with functional TR.
Table 1:
Hemodynamic and echocardiographic parameters before and after induction of FTR in PAB and TIC animals
| Pre-PAB | PAB | Pre-TIC | TIC | |
|---|---|---|---|---|
| TR (+0–4) | 0.4±0.5 | 3.2±1.2* | 0±0 | 3.1±0.9* |
| MR (+0–4) | 0±0 | 1.1±0.5* | 0±0 | 2.2±0.8* |
| RVFAC (%) | 54±4 | 38±7* | 54±7 | 37±9* |
| TAPSE | 1.2±0.1 | 0.8±0.1* | 1.3±0.2 | 1.1±0.3 |
| TAD (mm) | 2.4±0.2 | 3.1±0.2* | 2.5±0.3 | 3.2±0.5* |
| LV EF (%) | 63±3 | 58±4* | 62±8 | 33±8* |
mean±SD, TR= tricuspid regurgitation, MR= mitral regurgitation RVFAC= right ventricular fractional area contraction, TAPSE= tricuspid annulus plane systolic excursion, TAD= tricuspid annulus diameter, LVEF = left ventricular ejection fraction;
p<0.05 versus Pre- by Student’s t-test for dependent observations.
Table 2:
Hemodynamic parameters of all animal groups at the time of data collection during the terminal study
| CTL (n=8) | PAB (n=15) | TIC (n=14) | ANOVA (p) | |
|---|---|---|---|---|
| Weight (kg) | 63±4 | 63±3 | 57±5* | <0.001 |
| HR (bpm) | 88±11 | 108±16* | 126±13* | <0.001 |
| LVP (mmHg) | 98±11 | 88±18 | 91±16 | 0.355 |
| RVP (mmHg) | 30±7 | 45±15* | 39±10 | 0.015 |
| CVP (mmHg) | 12±1 | 12±2 | 19±5* | <0.001 |
mean±SD, HR= heart rate, LVP= left ventricular pressure, RVP= right ventricular pressure, CVP= central venous pressure;
p<0.05 versus CTL with Bonferroni correction.
Table 3:
Sonomicrometry-derived measurements of annular dynamics and geometry
| Control (n=8) | PAB (n=15) | TIC (n=14) | ANOVA (p) | ||
|---|---|---|---|---|---|
| TAA (mm2) | 651±109 | 886±242* | 995±232* | 0.006 | |
| TAA Contraction (%) | 16.6±4.2 | 11.5±8.0 | 6±4* | 0.003 | |
| CC Distance (mm) | AS-PS (1–5) | 28.8±2.8 | 32.2±5.0 | 35.3±2.6* | 0.003 |
| AS-AP (1–3) | 20.3±4.6 | 25.9±5.5* | 28.1±4.5* | 0.007 | |
| AP-PS (3–5) | 30.0±5.1 | 31.7±4.7 | 30.5±4.7 | 0.699 | |
| TA Diameter (mm) | A-P | 26.6±2.7 | 32.0±5.7* | 34.7±3.9* | 0.010 |
| S-L | 24.3±3.3 | 29.4±5.0* | 31.7±3.4* | 0.018 | |
| TAP (mm) | 95.8±8.1 | 107.7±15.3 | 114.5±9.5* | 0.007 | |
| TAP Contraction (%) | 7.4±1.7 | 5.5±3.8 | 3.5±2.7* | 0.027 | |
| Regional TAP (mm) | Anterior (1–2-3) | 28.7±4.9 | 32.6±7.4 | 35.6±5.6 | 0.075 |
| Posterior (3–4-5) | 36.3±6.4 | 38.1±6.0 | 36.1±4.4 | 0.615 | |
| Septal (5–6-1) | 33.7±3.1 | 39.7±6.4* | 43.1±3.2* | 0.001 | |
| Regional TAP Contraction (%) | Anterior (1–2-3) | 11.6±2.8 | 6.9±5.1 | 6.1±5.7* | 0.057 |
| Posterior (3–4-5) | 10.5±3.8 | 7.4±5.3 | 8.5±7.4 | 0.536 | |
| Septal (5–6-1) | 5.9±1.8 | 5.4±3.1 | 5.4±3.8 | 0.933 | |
mean±SD, TAA= tricuspid annular area, Contraction= % reduction during cardiac cycle, CC= commissure-commissure, AS= antero-septal, AP= antero-posterior, PS= posterior-septal, TA= tricuspid annulus, AP= anterior-posterior, SL= septal-lateral, TAP= tricuspid annular perimeter;
p<0.05 versus CTL by Student’s t-test for independent comparisons with Bonferroni correction.
Figure 2.
Group mean and standard deviation data for tricuspid annular area (top panel) and tricuspid annular perimeter (bottom panel) throughout the cardiac cycle in control (CTL=8 [black line]), pulmonary artery banding (PAB=15 [dashed blue line]) and tachycardia-induced cardiomyopathy (TIC=14 [dashed orange line]) animals. ED= end-diastole, EIVC= end-isovolumic contraction, ES= end-systole, EIVR= end-isovolumic contraction.
Figure 3.
Group mean and standard deviation data for anterior (top panel), posterior (middle panel) and septal (bottom panel) annular perimeter throughout the cardiac cycle in control (CTL=8 [black line]), pulmonary artery banding (PAB=15 [dashed blue line]) and tachycardia-induced cardiomyopathy (TIC=14 [dashed orange line]) animals. ED= end-diastole, EIVC= end-isovolumic contraction, ES= end-systole, EIVR= end-isovolumic contraction.
Figure 4.
Tricuspid annular strain for control (CTL=8 [top panel]), pulmonary artery banding (PAB=15 [middle panel]) and tachycardia-induced cardiomyopathy (TIC=14 [bottom panel]) animals at end-diastole (ED), end-isovolumic contraction (EIVC), end-systole (ES), and end-isovolumic relaxation (EIVR) versus maximal diastolic annular size. AS= anterior septal commissure, AP= anterior-posterior commissure, and PS= posterior septal commissure. Red color indicates contraction, blue elongation.
Discussion
Dilation of the tricuspid annulus is central to the pathophysiology of functional tricuspid regurgitation, yet the detailed three-dimensional geometry and dynamics of the tricuspid annulus associated with FTR have not been fully characterized. Our experimental study using two different ovine models of FTR revealed significant annular area increase, reduced dynamic motion, and pronounced enlargement of the septal portion of the annulus.
The ovine model of pulmonary banding used in the study resulted in isolated RV dysfunction and moderately severe FTR which is consistent with prior studies.9 Rapid ventricular pacing on the other hand was used to induce an ovine model of FTR in the setting of biventricular failure.7 Echocardiographic findings in both models demonstrated reduced RV function, chamber enlargement, and annular dilatation all consistent with experimental observations of other investigators11 and clinical reports in patients with functional TR.12 Recent three-dimensional echocardiographic assessment of normal human TV annulus revealed 35±10% area reduction during the cardiac cycle with maximal size observed in late diastole prior to atrial contraction.13 We also found maximal TA area in late diastole with significant pre-systolic contraction present as observed clinically. However, our TA area reduction of 16% in control animals was not as remarkable but similar to that reported with sonomicrometry in pig (21%)14 and sheep (22%)15 experiments as well as ex vivo human hearts (11%).16 Two- and three-dimensional echocardiographic studies of normal and dilated human hearts with at least moderate FTR have revealed that annular area increased by approximately 50% with greater circularization of annular shape.17,18 These observations are consistent with our findings of approximately 36–52% annular increase at end-systole. Additionally, annular area contraction was significantly reduced in patients with FTR17 as demonstrated in our study. Both anterior-posterior and septal lateral annular diameters increased with FTR although more remarkably in TIC. These geometrical perturbations and changes in annular eccentricity are consistent with clinical findings in patients.17,19
The basis for annuloplasty reduction of the tricuspid anulus to treat FTR were derived from anatomical studies of Acar2 who found that annular dilation in FTR occurred predominantly in the anterior and posterior portion of the annulus. However, these early pathologic studies included only 10 normal hearts and 15 hearts with rhematic heart disease and functional TR and may therefore not represent the full spectrum of anatomical variations. A recent pathologic study of the tricuspid valve in 100 hearts without valvular disease20 revealed significant variation in annular anatomy. In particular, the posterior annulus length may range from 26% to 45% of total annular circumference depending on the number of posterior leaflet scallops which may vary from one to three. A smaller anatomical study of 27 normal hearts confirmed posterior leaflet scallop heterogeneity and established the posterior segment of the annulus as the largest annular segment.21 However, the exact position of the anterior-posterior commissure remains difficult to standardize.5,20,21 These data are consistent with our ovine findings with the posterior being the largest segment of the annulus in control animals. However, we were surprised to find that the septal annulus dilated remarkably in both our ovine models of RV failure and FTR. Interestingly, septal dilation was significantly greater in the setting of biventricular failure versus isolated right ventricular dysfunction suggesting that left sided myocardial compromise may further contribute to tricuspid annular dilation. Our prior acute ovine studies with mechanical unloading of the left ventricle22 revealed reduction in tricuspid septal annular length suggesting an influence of left ventricular chamber size on the septal annulus and corroborating current data. A recent clinical study supports our experimental findings.5 Direct intra-operative measurements of the tricuspid annulus in 317 patients with varying degrees of FTR reported that all segments of the tricuspid annulus dilate during progression from mild to severe FTR with 11.4% dilation in the septal annulus. It is feasible that this increase is substantially greater versus normal human hearts as a healthy control group was not included in the study. Similarly, Kabasawa and colleagues23 reported that on pre-operative CT imaging of patients undergoing TV repair the tricuspid annulus dilated in all segments proportionally. The septal annulus was found to be the longest of the three annular segments in patients with severe FTR in the study by Teng5 confirming our findings. Furthermore, dilation of the septal annulus was also reported to be the most sensitive predictor of post-operative recurrence of FTR which may have implications for valvular repair. Although ring annuloplasty has been shown to be effective in patients with moderate or less FTR24, prosthetic annular reduction of severe FTR if fraught with high residual and recurrent TR rates.3 Use of the rigid classic Carpenier-Edwards ring has been shown to offer better control of FTR progression in one study4 which may be related to its structure or more complete support of the annulus. In annuloplasty repair of severe FTR, Rodriguez-Palomares26 reported pre-discharge moderate or greater residual TR in 32.5% of patients with 12.5% being severe. Most of the currently utilized tricuspid annular prostheses leave a variable portion of the septal annulus unsupported6, and progressive dilation may contribute to recurrent insufficiency. To this end, alterations of surgical technique have been introduced to better support the sepal annulus when performing prosthetic annular reduction in severe FTR.26,27 Although these studies include only few patients, they have thus far yielded low recurrence rates at mid-term follow-up. Use of complete ring annuloplasty and septal plication was also demonstrated to be effective in correcting TR in a patient with massive annular dilation and FTR.28 Based on the above data, the adequacy of open annuloplasty bands to treat severe FTR with annular dilation may need re-evaluation and alternative surgical techniques or valve replacement warrant deliberation. Likewise, using the length of the septal annulus for sizing annuloplasty devices may also need reassessment. Surgically, septal plication and use of complete rings could be considered to better stabilize the septal annulus and potentially improve control of FTR based on the current data, however our study did not investigate any reparative techniques or their outcomes.
In conclusion, our experimental study using two ovine models of functional tricuspid regurgitation revealed annular dilation and reduction of annular dynamics consistent with clinical findings in patients with significant FTR. We found that all segments of the tricuspid annulus dilated during evolution of FTR but surprising most remarkably in the septal portion of the annulus which was further exacerbated by left sided dysfunction. These data may shed new light on the high failure rates of isolated annuloplasty repair of severe tricuspid regurgitation and guide more rational prosthesis design and novel reparative techniques to treat FTR.
Limitations
Our study has several important limitations that warrant caution in clinical extrapolation of these results. The data were collected in open-chest animals under general anesthesia which can have a significant impact on RV function and TV dynamics, yet our prior studies in awake and anesthetized sheep did not show large effects on annular dynamics.29 Pulmonary artery banding was used to establish right ventricular pressure overload with associated RV dysfunction and FTR and as such does not reflect clinical disease. However, experimental afterload-based models may be more reliable to induce FTR as clinical studies have shown that volume overload even when associated with RV dilation does not lead to significant valvular insufficiency.30 Our model of FTR associated with tachycardia induced cardiomyopathy presents a rare form of clinical tricuspid regurgitation and was induced over a three-week period again not reflecting clinical practice. Overall, the geometric changes in the tricuspid valve apparatus found in our models reflect clinical findings, and as experimental tool these models permit evaluation of annular geometry and dynamics in FTR with and without associated left sided dysfunction. Clinical extrapolation requires restraint as sheep and human tricuspid annulus may differ in anatomy and dynamics, but our previous sonomicrometry experiments in isolated normal beating human hearts16 have shown similar annular dynamics and geometry to that seen in sheep in-vivo.21 An additional limitation of our study lies in the design that did not permit acquisition of baseline sonomicrometry data in all groups or examine surgical treatment options.
Supplementary Material
Supplemental Figure 1. Group mean and standard deviation data for anterior-posterior (top panel) and septal-lateral (middle panel) annular diameters and annular eccentricity (bottom panel) throughout the cardiac cycle for CTL (black line), PAB (dashed blue line) and TIC (dashed orange line) animals. ED= end-diastole, EIVC= end-isovolumic contraction, ES= end-systole, EIVR= end-isovolumic contraction.
Supplemental Figure 2. Group mean and standard deviation for position of each annular crystal from the least squares annular plane (dashed line) at end-diastole (top panel) and end-systole (bottom panel) for CTL (black line), PAB (dashed blue line) and TIC (dashed orange line) animals.
Video 1. Video images of epicardial echocardiography at the time of the terminal study in a PAB (left panel) and a TIC (right panel) animal.
Figure 5.
Graphic summary of experimental methods and key findings of the study
Central Picture.
Septal annulus throughout the cardiac cycle in CTL, PAB, and TIC animals.
Central Message.
Chronic ovine FTR with and without left ventricular dysfunction was associated with significant tricuspid annular dilation and lengthening of the septal portion of the annulus.
Perspective Statement.
Currently utilized annuloplasty bands used to treat FTR leave variable portion of the septal annulus unsupported. Our data suggest that the septal annulus dilates significantly in severe FTR and may contribute to high recurrence rates. These data may better guide design of annuloplasty prostheses.
Funding:
The study was funded by internal grant from the Meijer Heart and Vascular Institute at Corewell Health and National Institute of Health R01HL165251 (MKR and TAT) and R21HL161832 (MKR and TAT).
Glossary of Abbreviations
- CPB
Cardiopulmonary bypass
- CTL
Control
- ED
End-diastole
- ES
End-systole
- FTR
Functional tricuspid regurgitation
- LV
Left ventricle
- PAB
Pulmonary artery banding
- RV
Right ventricle
- TA
Tricuspid annulus
- TIC
Tachycardia Induced Cardiomyopathy
Footnotes
Disclosures: The authors have no disclosures associated with this manuscript
IACUC: Calvin University Institutional Animal Care and Use Committee protocol number 2018–438 and Michigan State University Protocol 2020–35 approved on 7/27/2020.
Artur Iwasieczko and Tomasz Jazwiec were Peter C. and Pat Cook Endowed Research Fellows in Cardiothoracic Surgery.
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Associated Data
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Supplementary Materials
Supplemental Figure 1. Group mean and standard deviation data for anterior-posterior (top panel) and septal-lateral (middle panel) annular diameters and annular eccentricity (bottom panel) throughout the cardiac cycle for CTL (black line), PAB (dashed blue line) and TIC (dashed orange line) animals. ED= end-diastole, EIVC= end-isovolumic contraction, ES= end-systole, EIVR= end-isovolumic contraction.
Supplemental Figure 2. Group mean and standard deviation for position of each annular crystal from the least squares annular plane (dashed line) at end-diastole (top panel) and end-systole (bottom panel) for CTL (black line), PAB (dashed blue line) and TIC (dashed orange line) animals.
Video 1. Video images of epicardial echocardiography at the time of the terminal study in a PAB (left panel) and a TIC (right panel) animal.