Model Of Aortic Regurgitation Research Articles

Impact of heart rate, aortic compliance and stroke volume on the aortic regurgitation fraction studied in an ex vivo pig model

IntroductionDrug therapy to reduce the regurgitation fraction (RF) of high-grade aortic regurgitation (AR) by increasing heart rate (HR) is generally recommended. However, chronic HR reduction in HFREF patients can significantly...

Modified Heterotopic Abdominal Heart Transplantation and a Novel Aortic Regurgitation Model in Rats.

Over the past 50 years, many researchers have reported heterotopic abdominal heart transplantation in mice and rats, with some variations in the surgical technique. Modifying the transplantation procedure to strengthen the myocardial protection could prolong the ischemia time while preserving the donor's cardiac function. This technique's key points are as follows: transecting the donor's abdominal aorta before harvesting to unload the donor's heart; perfusing the donor's coronary arteries with a cold cardioplegic solution; and topical cooling of the donor's heart during the anastomosis procedure. Consequently, since this procedure prolongs the acceptable ischemia time, beginners can easily perform it and achieve a high success rate. Moreover, a new aortic regurgitation (AR) model was established in this work using a technique different from the existing one,which is created by inserting a catheter from the right carotid artery and puncturing the native aortic valve under continuous echocardiographic guidance. A heterotopic abdominal heart transplantation was performed using the novel AR model. In the protocol, after the donor's heart is harvested, a stiff guidewire is inserted into the donor's brachiocephalic artery and advanced toward the aortic root. The aortic valve is punctured by pushing the guidewire further even after the resistance is felt, thus inducing AR. It is easier to damage the aortic valve using this method than with the procedure described in the conventional AR model. Additionally, this novel AR model does not contribute to the recipient's circulation; therefore, this method is expected to produce a more severe AR model than the conventional procedure.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Surgically Induced Cardiac Volume Overload by Aortic Regurgitation in Mouse.

Aortic regurgitation (AR) is a common valvular heart disease that exerts volume overload on the heart and represents a global public health problem. Although mice are widely applied to shed light on the mechanisms of cardiovascular disease, mouse models of AR, especially those induced by surgery, are still paucity. Here, a mouse model of AR was described in detail which is surgically induced by disruption of the aortic valves under high-resolution echocardiography. In accordance with regurgitated blood flow, AR mouse hearts present a distinctive and clinically relevant volume overload phenotype, which is characterized by eccentric hypertrophy and cardiac dysfunction, as evidenced by echocardiographic and invasive hemodynamic evaluation. Our proposal, in a reliable and reproducible manner, provides a practical guide on the establishment and assessment of a mouse model of AR for future studies on molecular mechanisms and therapeutic targets of volume overload cardiomyopathy.

In vitro Assessment of Aortic Regurgitation Using Four-Dimensional Flow Magnetic Resonance Imaging.

Aortic regurgitation (AR) refers to backward blood flow from the aorta into the left ventricle (LV) during ventricular diastole. The regurgitant jet arising from the complex shape is characterized by the three-dimensional flow and high-velocity gradient, sometimes limiting an accurate measurement of the regurgitant volume using 2D echocardiography. Recently developed four-dimensional flow magnetic resonance imaging (4D flow MRI) enables three-dimensional volumetric flow measurements, which can be used to accurately quantify the amount of the regurgitation. This study focuses on (i) magnetic resonance compatible AR model fabrication (dilatation, perforation, and prolapse) and (ii) systematic analysis of the performance of 4D flow MRI in AR quantification. The results indicated that the formation of the forward and backward jets over time was highly dependent on the types of AR origin. The amount of regurgitation volume bias for the model types were -7.04%, -33.21%, 6.75%, and 37.04% compared to the ground truth (48 mL) volume measured from the pump stroke volume. The largest error of the regurgitation fraction was around 12%. These results indicate that careful selection of imaging parameters is required when absolute regurgitation volume is important. The suggested in vitro flow phantom can easily be modified to simulate other valvular diseases such as aortic stenosis or bicuspid aortic valve (BAV) and can be used as a standard platform to test different MRI sequences in the future.

<em>In vitro</em> Assessment of Aortic Regurgitation Using Four-Dimensional Flow Magnetic Resonance Imaging

Aortic regurgitation (AR) refers to backward blood flow from the aorta into the left ventricle (LV) during ventricular diastole. The regurgitant jet arising from the complex shape is characterized by the three-dimensional flow and high-velocity gradient, sometimes limiting an accurate measurement of the regurgitant volume using 2D echocardiography. Recently developed four-dimensional flow magnetic resonance imaging (4D flow MRI) enables three-dimensional volumetric flow measurements, which can be used to accurately quantify the amount of the regurgitation. This study focuses on (i) magnetic resonance compatible AR model fabrication (dilatation, perforation, and prolapse) and (ii) systematic analysis of the performance of 4D flow MRI in AR quantification. The results indicated that the formation of the forward and backward jets over time was highly dependent on the types of AR origin. The amount of regurgitation volume bias for the model types were -7.04%, -33.21%, 6.75%, and 37.04% compared to the ground truth (48 mL) volume measured from the pump stroke volume. The largest error of the regurgitation fraction was around 12%. These results indicate that careful selection of imaging parameters is required when absolute regurgitation volume is important. The suggested in vitro flow phantom can easily be modified to simulate other valvular diseases such as aortic stenosis or bicuspid aortic valve (BAV) and can be used as a standard platform to test different MRI sequences in the future.

The Role of Extracellular Matrix in the Experimental Acute Aortic Regurgitation Model in Rats

Mechanisms involved in cardiac remodelling by aortic regurgitation (AR) and the moment when cardiac dysfunction begins are largely unknown. This study aimed to investigate cardiac morphology and function after 1, 4, 8, and 12 weeks of experimental AR in Wistar rats. Extracellular matrix was also investigated as the potential mechanism that underlies the AR remodelling process. Male Wistar rats underwent surgical acute AR (AR group, n=51) or a sham surgery (sham group, n=32). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 12 weeks. Morphometry of cardiac tissue and the activities of metalloproteinase 2 (MMP-2) and tissue metalloproteinase inhibitor-1 (TIMP-1) were analysed. Statistical analysis was performed by two-way ANOVA. Significance level was 5%. The AR group presented an increase in the sphericity index (week 1); an increase in the left atrium, left ventricular mass index, TIMP-1 and MMP-2 activities, and collagen fraction (week 4); an increase in myocyte area (week 8); and a reduction in fraction shortening (week 12). First, the chamber became more spherical; second, MMP-2 and TIMP-1 were activated and this may have contributed to hypertrophy and atrial enlargement, until systolic dysfunction occurred. This study showed a sequence of abnormalities that preceded myocardial dysfunction in an experimental model of AR. First, haemodynamic volume overload led to a more spherical left ventricle chamber. Second, MMP-2 and TIMP-1 transitorily increased and may have contributed to atrial enlargement, eccentric hypertrophy, and systolic dysfunction.

Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice.

Aortic regurgitation (AR) is a volume overload disease causing eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis is involved in many cardiovascular diseases, but whether they also participate in AR-induced heart failure is still elusive. In this study, we found ER stress activation in myocardial samples from patients with AR. With a unique murine model of AR which induced eccentric cardiac hypertrophy and heart failure, we also found aggravation of cardiac ER stress and apoptosis, as evidenced by a reduction of Bcl-2/Bax ratio and an increase of caspase-3 cleavage. We then examined the signaling effectors involved in ER-initiated apoptosis and found volume overload specifically activated C/EBP homologous protein (CHOP), but not caspase-12 or Jun N-terminal kinase (JNK). Interestingly, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved cardiac function, and suppressed ER stress, apoptosis, and CHOP. Furthermore, genetic knockdown of CHOP inhibited cardiac Bcl-2/Bax ratio reduction and caspase-3 activation and rescued cardiac dysfunction. In summary, our findings suggest that ER stress-CHOP signaling is involved in the development of volume overload cardiac hypertrophy induced by AR through promoting cardiomyocytes apoptosis and provide a previously unrecognized target in heart failure induced by volume overload.

The myosin activator omecamtiv mecarbil improves wall stress in a rat model of chronic aortic regurgitation.

In patients with chronic aortic regurgitation (AR), excessive preload and afterload increase left ventricle wall stress, leading to left ventricular systolic dysfunction. Thus, the objective of the present study was to evaluate the effects of the myosin activator omecamtiv mecarbil (OM) on left ventricle wall stress in an experimental rat model of severe chronic AR. Forty adult male Wistar rats were randomized into two experimental groups: induction of AR (acute phase) by retrograde puncture (n = 34) or a sham intervention (n = 6). Rats that survived the acute phase (n = 18) were randomized into an OM group (n = 8) or a placebo group (n = 10). Equal volumes of OM (1.2 mg/kg/h) or placebo (0.9% NaCl) were continuously infused into the femoral vein over 30 min. OM significantly decreased end‐systolic and end‐diastolic and maximum wall stress in this experimental rat model of chronic severe AR (p < 0.001) and increased systolic performance assessed by fractional shortening and left ventricle end‐systolic diameter; both p < 0.05). These effects were correlated with decreased indices of global cardiac function (cardiac output and stroke volume; p < 0.05) but were not inferior to baseline pump indices. Infusion with placebo did not affect global cardiac function but decreased end‐systolic wall stress (p < 0.05) and increased systolic performance (all p < 0.001). In the sham‐operated (control) group, OM decreased diastolic wall stress (p < 0.05). Based on these results, OM had a favorable effect on left ventricle wall stress in an experimental rat model of severe chronic AR.

A Novel Aortic Regurgitation Model from Cusp Prolapse with Hemodynamic Validation Using an Ex Vivo Left Heart Simulator.

Although ex vivo simulation is a valuable tool for surgical optimization, a disease model that mimics human aortic regurgitation (AR) from cusp prolapse is needed to accurately examine valve biomechanics. To simulate AR, four porcine aortic valves were explanted, and the commissure between the two largest leaflets was detached and re-implanted 5mm lower to induce cusp prolapse. Four additional valves were tested in their native state as controls. All valves were tested in a heart simulator while hemodynamics, high-speed videography, and echocardiography data were collected. Our AR model successfully reproduced cusp prolapse with significant increase in regurgitant volume compared with that of the controls (23.2 ± 8.9 versus 2.8 ± 1.6ml, p = 0.017). Hemodynamics data confirmed the simulation of physiologic disease conditions. Echocardiography and color flow mapping demonstrated the presence of mild to moderate eccentric regurgitation in our AR model. This novel AR model has enormous potential in the evaluation of valve biomechanics and surgical repair techniques. Graphical Abstract.

Proof of Concept: Echo Compatible Mock-Circulatory Flow Loop to Accurately Quantify Aortic Regurgitation in Patients with Left Ventricular Assist Devices

Aortic regurgitation (AR) in patients with Left ventricular assist devices (LVAD) is associated with poor outcome and decreased device durability. Accurate quantification of aortic regurgitation in patients with LVAD by echocardiography has been a challenge, particularly since there is no gold standard for accurate regurgitant volume estimation. Therefore, the aim of our study was to develop a mock-circulatory flow loop using patient specific 3D model that allows accurate assessment of AR by flow meters. Using a cardiac CT from a patient with LVAD and aortic regurgitation, a 3D model was printed. A pulsatile flow loop system and HeartMate II LVAD was connected to 3D model and we were able to accurately simulate LV and Aortic pressure (figure 1). Aortic regurgitant volume (RV) was quantified at various LVAD speeds. The AR volume was quantified at increments of 200 RPM. At baseline speed of 8000 RPM, the regurgitant volume was 34 cc and with each increment in speed the RV increased proportionally. This system is echo compatible and the in vitro echocardiographic evaluation of AR severity is being developed CONCLUSION: We have created patient specific model of AR in a flow system with LVAD support. Thus far we have demonstrated that RV varies directly with level of LVAD support.

Hypertrophy Signaling Pathways in Experimental Chronic Aortic Regurgitation

The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one or two valve cusps, resulting in eccentric remodeling and left ventricular dysfunction, with no increase in overall fibrosis. Western blotting showed increased activation of Akt and p38 at 12weeks and of c-Jun amino-terminal kinase at 2weeks, decreased activation of extracellular regulated kinase 5 at both 2 and 12weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy.

Comparative Study of Vasodilators in an Animal Model of Chronic Volume Overload Caused by Severe Aortic Regurgitation

Background— Aortic regurgitation (AR) is a disease of chronic left ventricular (LV) volume overload. Over time, AR will lead to LV dilatation, hypertrophy, and loss of function. There is currently no medical treatment proven effective to slow the evolution of this cardiomyopathy. Vasodilators were once thought to have protective effects, but recent publications have cast some doubts about their effectiveness. We hypothesized that drugs targeting the renin-angiotensin system should be more effective than those having no direct effect on the renin-angiotensin system. Methods and Results— We designed a protocol comparing the effects of 3 vasodilators in a rat AR model (n=9 to 11 animals per group). The effects of a 6-month treatment of (1) nifedipine, (2) captopril, or (3) losartan were compared in male AR rats. Sham-operated and untreated AR animals were used as controls. Nifedipine-treated animals displayed hemodynamics, LV dilatation, hypertrophy, and loss of function similar to those of the untreated group. Both captopril and losartan were effective in improving hemodynamics, slow LV dilatation, hypertrophy, and dysfunction. Gene expression analysis confirmed the lack of effects of the nifedipine treatment at the molecular level. Conclusions— Using an animal model of severe AR, we found that vasodilators targeting the renin-angiotensin system were effective to slow the development of LV remodeling and to preserve LV function. As recently shown in the most recent human clinical trial, nifedipine was totally ineffective. Targeting the renin-angiotensin system seems a promising avenue in the treatment of this disease, and clinical trials should be carefully designed to re-evaluate the effectiveness of angiotensin I–converting enzyme inhibitors or angiotensin II receptor blockers in AR.

Genetic Disruption of Angiotensin II Type 1a Receptor Improves Long-Term Survival of Mice With Chronic Severe Aortic Regurgitation

Aortic regurgitation (AR) causes left ventricular (LV) volume overload, leading to progressive LV dilatation and dysfunction. In the present study it was examined whether blockade of angiotensin II type 1 receptor (AT1) could improve survival in cases of chronic severe AR. AR was induced by puncturing the aortic valves of wild-type (WT) and AT1a knockout (KO) mice. Mice that survived for 4 weeks after the operation were deemed to be a model of chronic severe AR and were followed up for 50 weeks (WT, n=29; KO, n=31). Baseline measurements made 4 weeks after surgery showed similar LV cavity and function in both genotypes. These conditions progressively worsened in both genotypes, but 16 weeks after baseline, KO mice showed significantly less LV dilatation, hypertrophy and interstitial fibrosis than WT mice. Cardiac mRNA expression of B-type natriuretic peptide and type I collagen was lower in KO than WT mice. The 50-week mortality rate was significantly lower among KO (45.2%) than WT (86.2%) mice, and postmortem findings indicated that the lower mortality was attributable to a lower incidence of congestive heart failure. In cases of chronic severe AR, blockade of AT1 attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival.

Importance of mitral valve repair associated with left ventricular reconstruction for patients with ischemic cardiomyopathy: a real-time three-dimensional echocardiographic study

Background: For evaluating patients with aortic regurgitation (AR), regurgitant volumes, left ventricular (LV) stroke volumes (SV), and absolute LV volumes are valuable indices. Aim: The aim of this study was to validate the combination of real-time 3-dimensional echocardiography (3DE) and semiautomated digital color Doppler cardiac flow measurement (ACM) for quantifying absolute LV volumes, LVSV, and AR volumes using an animal model of chronic AR and to investigate its clinical applicability. Methods: In 8 sheep, a total of 26 hemodynamic states were obtained pharmacologically 20 weeks after the aortic valve noncoronary (n = 4) or right coronary (n = 4) leaflet was incised to produce AR. Reference standard LVSV and AR volume were determined using the electromagnetic flow method (EM). Simultaneous epicardial real-time 3DE studies were performed to obtain LV end-diastolic volumes (LVEDV), end-systolic volumes (LVESV), and LVSV by subtracting LVESV from LVEDV. Simultaneous ACM was performed to obtain LVSV and transmitral flows; AR volume was calculated by subtracting transmitral flow volume from LVSV. In a total of 19 patients with AR, real-time 3DE and ACM were used to obtain LVSVs and these were compared with each other. Results: A strong relationship was found between LVSV derived from EM and those from the real-time 3DE (r = 0.93, P <.001, mean difference (3D − EM) = −1.0 ± 9.8 mL). A good relationship between LVSV and AR volumes derived from EM and those by ACM was found (r = 0.88, P <.001). A good relationship between LVSV derived from real-time 3DE and that from ACM was observed (r = 0.73, P <.01, mean difference = 2.5 ± 7.9 mL). In patients, a good relationship between LVSV obtained by real-time 3DE and ACM was found (r = 0.90, P <.001, mean difference = 0.6 ± 9.8 mL). Conclusion: The combination of ACM and real-time 3DE for quantifying LV volumes, LVSV, and AR volumes was validated by the chronic animal study and was shown to be clinically applicable. (J Am Soc Echocardiogr 2002;15:966-71.)

Quantitative analysis of aortic regurgitation: Real-time 3-dimensional and 2-dimensional color Doppler echocardiographic method—a clinical and a chronic animal study

Background: For evaluating patients with aortic regurgitation (AR), regurgitant volumes, left ventricular (LV) stroke volumes (SV), and absolute LV volumes are valuable indices. Aim: The aim of this study was to validate the combination of real-time 3-dimensional echocardiography (3DE) and semiautomated digital color Doppler cardiac flow measurement (ACM) for quantifying absolute LV volumes, LVSV, and AR volumes using an animal model of chronic AR and to investigate its clinical applicability. Methods: In 8 sheep, a total of 26 hemodynamic states were obtained pharmacologically 20 weeks after the aortic valve noncoronary (n = 4) or right coronary (n = 4) leaflet was incised to produce AR. Reference standard LVSV and AR volume were determined using the electromagnetic flow method (EM). Simultaneous epicardial real-time 3DE studies were performed to obtain LV end-diastolic volumes (LVEDV), end-systolic volumes (LVESV), and LVSV by subtracting LVESV from LVEDV. Simultaneous ACM was performed to obtain LVSV and transmitral flows; AR volume was calculated by subtracting transmitral flow volume from LVSV. In a total of 19 patients with AR, real-time 3DE and ACM were used to obtain LVSVs and these were compared with each other. Results: A strong relationship was found between LVSV derived from EM and those from the real-time 3DE (r = 0.93, P <.001, mean difference (3D − EM) = −1.0 ± 9.8 mL). A good relationship between LVSV and AR volumes derived from EM and those by ACM was found (r = 0.88, P <.001). A good relationship between LVSV derived from real-time 3DE and that from ACM was observed (r = 0.73, P <.01, mean difference = 2.5 ± 7.9 mL). In patients, a good relationship between LVSV obtained by real-time 3DE and ACM was found (r = 0.90, P <.001, mean difference = 0.6 ± 9.8 mL). Conclusion: The combination of ACM and real-time 3DE for quantifying LV volumes, LVSV, and AR volumes was validated by the chronic animal study and was shown to be clinically applicable. (J Am Soc Echocardiogr 2002;15:966-71.)

Fibrosis, Myocyte Degeneration and Heart Failure in Chronic Experimental Aortic Regurgitation

Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 ± 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 ± 0.8 years (range 0.6–2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 ± 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.