Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation.

BACKGROUND: Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. METHODS: Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n = 4) or 9 (n = 4) weeks after Sugen5416 and hypoxia and 12 weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. RESULTS: In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. CONCLUSIONS: Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Pulmonary artery banding is a relevant model to study the right ventricular remodeling and dysfunction that occurs in pulmonary arterial hypertension.

Right ventricular (RV) dysfunction determines mortality in patients with pulmonary arterial hypertension (PAH) and RV pressure loading. Experimental models commonly use Sugen hypoxia (SuHx)-induced PAH, monocrotaline (MCT)-induced PAH, or pulmonary artery banding (PAB). Because PAH models cannot interrogate RV effects or therapies independent of pulmonary vascular effects, we aimed to compare RV function and fibrosis in experimental PAB vs. PAH. Thirty rats were randomized to either sham controls, PAB, SuHx-, or MCT-induced PAH. RV pressures and function were assessed by high-fidelity pressure-tipped catheters and by echocardiography. RV myocyte hypertrophy, fibrosis, and capillary density were quantified from hematoxylin-eosin, picrosirius red-stained, and CD31-immunostained RV sections, respectively. RV pressures and the RV-to-left ventricular pressure ratio were significantly increased in all three groups to a similar degree (PAB 65 ± 17 mmHg, SuHx 72 ± 16 mmHg, and MCT 70 ± 12 mmHg) vs. controls (23 ± 2 mmHg, all P < 0.01). RV dilatation, hypertrophy, and fibrosis were similarly increased, and capillary density decreased, in the three models (RV fibrosis; PAB 13.3 ± 3.6%, SuHx 9.8 ± 3.0% and MCT 10.9 ± 2.4% vs control 5.5 ± 1.1%, all P < 0.05). RV function was similarly decreased in all models vs. controls. We observed comparable RV dilatation, hypertrophy, systolic and diastolic dysfunction, fibrosis, and capillary rarefaction in rat models of PAB, SuHx-, and MCT-induced PAH. These results suggest that PAB, when sufficiently severe, induces features of maladaptive RV remodeling and can be used to investigate RV pathophysiology and therapy effects independent of pulmonary vascular resistance.NEW & NOTEWORTHY Although animal models of pulmonary arterial hypertension and pressure loading are important to study right ventricular (RV) pathophysiology, pulmonary arterial hypertension models cannot interrogate RV responses independent of pulmonary vascular effects. Comparing three commonly used rat models under similar elevated RV pressure, we found that all models resulted in comparable maladaptive RV remodeling and dysfunction. Thus, these findings suggest that the pulmonary artery banding model can be used to investigate mechanisms of RV dysfunction in RV pressure overload and the effect of potential therapies.

Essential Modifiers of Double Outlet Right Ventricle: Revisit With Endocardial Surface Images and 3-Dimensional Print Models.

Hearts with double outlet right ventricle are a heterogeneous group of malformations in which a comprehensive diagnostic approach is required for tailored surgical management. This pictorial essay revisits essential modifiers of clinical and surgical importance in management of the patients with double outlet right ventricle using 3-dimensional volume-rendered endocardial surface images and 3-dimensional print models. Special emphasis is paid to the infundibular morphology, including the size and orientation of the outlet septum, relative to the margin of the ventricular septal defect, and the extent of the muscular infundibulum as an additional modifier of the distance between the ventricular septal defect margin and the arterial valve or valves.

3D printing in medicine of congenital heart diseases.

Congenital heart diseases causing significant hemodynamic and functional consequences require surgical repair. Understanding of the precise surgical anatomy is often challenging and can be inadequate or wrong. Modern high resolution imaging techniques and 3D printing technology allow 3D printing of the replicas of the patient's heart for precise understanding of the complex anatomy, hands-on simulation of surgical and interventional procedures, and morphology teaching of the medical professionals and patients. CT or MR images obtained with ECG-gating and breath-holding or respiration navigation are best suited for 3D printing. 3D echocardiograms are not ideal but can be used for printing limited areas of interest such as cardiac valves and ventricular septum. Although the print materials still require optimization for representation of cardiovascular tissues and valves, the surgeons find the models suitable for practicing closure of the septal defects, application of the baffles within the ventricles, reconstructing the aortic arch, and arterial switch procedure. Hands-on surgical training (HOST) on models may soon become a mandatory component of congenital heart disease surgery program. 3D printing will expand its utilization with further improvement of the use of echocardiographic data and image fusion algorithm across multiple imaging modalities and development of new printing materials. Bioprinting of implants such as stents, patches and artificial valves and tissue engineering of a part of or whole heart using the patient's own cells will open the door to a new era of personalized medicine.

Losartan ameliorates "upstream" pulmonary vein vasculopathy in a piglet model of pulmonary vein stenosis.

OBJECTIVES: Pulmonary vein stenosis (PVS) is a relentless disease with a poor prognosis. Although surgical repair can effectively treat "downstream" (near left atrial junction) PVS, residual "upstream" (deep in lung parenchyma) PVS commonly dictates long-term survival. Our initial studies revealed an association between PVS and transforming growth factor-ß signaling, which led us to investigate the effect of losartan on upstream pulmonary vein vasculopathy in a piglet model of PVS. METHODS: Neonatal Yorkshire piglets underwent sham surgical banding (sham, n = 6), staged bilateral pulmonary vein banding of all pulmonary veins except the right middle pulmonary vein (banded, n = 6), and staged pulmonary vein banding with losartan treatment (losartan, 1 mg/kg/d, n = 7). After 7 weeks, the hemodynamic data were obtained and the piglets killed. RESULTS: Pulmonary vein banding (compared with sham) was associated with continuous turbulent flow in banded pulmonary veins, pulmonary hypertension (pulmonary artery/systemic blood pressure ratio 0.51 ± 0.06 vs 0.23 ± 0.02, P < .001), and diffuse pulmonary vein intimal hyperplasia in the upstream pulmonary veins (P < .001). Losartan administration decreased the pulmonary artery/systemic blood pressure ratios compared with those in the banded piglets (0.36 ± 0.08 vs 0.51 ± 0.06, P = .007) but it remained greater than those in the sham group (P = .001). Losartan was also associated with diminished pulmonary vein intimal hyperplasia compared with that in the banded piglets (P < .001) but still remained more than that in the sham group (P = .035). Pulmonary vein banding reduced vascular endothelial-cadherin expression, indicative of diminished endothelial integrity, which was restored with losartan. CONCLUSIONS: Losartan treatment improved PVS-associated pulmonary hypertension and intimal hyperplasia and might be a beneficial prophylactic therapy for patients at high risk of developing PVS after pulmonary vein surgery.

Functional and pathological characteristics of reversible remodeling in a canine right ventricle in response to volume overloading and volume unloading.

PURPOSES: Patients who undergo right ventricular (RV) outflow augmentation inevitably develop RV remodeling due to pulmonary insufficiency-related volume overload (VOL). However, the reversibility of this remodeling is not fully understood. The goal of this study was to establish an animal model of VOL and unloading to characterize the functional and pathological characteristics and reversibility of RV remodeling. METHODS: VOL-RV was successfully induced by establishing direct RV-pulmonary artery (PA) bypass for 12 weeks in beagle canines. There were no procedure-related mortalities (n = 8). RESULTS: The RV developed typical functional features of VOL-related remodeling, such as a significant increase in end-diastolic/systolic volume and end-systolic pressure and a significant reduction in ejection fraction at 12 weeks, as assessed by three-dimensional echocardiography and cardiac catheterization. The RV developed typical pathological signs of remodeling, microstructural disorganization of cardiomyocytes, and/or structural/functional deterioration of the mitochondria. Volume unloading by division of the RV-PA bypass reversed the increase in the end-systolic/diastolic volume over 4 weeks when compared with a sham operation (n = 4 each). In addition, the bypass division also reversed the pathological changes seen in VOL-RV. CONCLUSIONS: VOL-RV that yielded typical functional and pathological features of RV remodeling was reproducibly achieved by direct RV-PA bypass in canines. The RV remodeling due to VOL was functionally and pathologically reversed by volume unloading via the bypass division.

First pediatric heart transplantation from a pediatric donor heart in Japan.

BACKGROUND: Since the revision of the Japanese Organ Transplantation Act, children younger than 15 years old can donate their organs after brain death. METHODS AND RESULTS: A teenage boy with endstage restrictive cardiomyopathy underwent the first heart transplantation with a pediatric donor heart in Japan on April 12, 2011. He had a good postoperative clinical course and no histological rejection episodes. His waiting period was relatively short (237 days) compared with adult patients, because of the pediatric patient-first policy for a pediatric donor heart. CONCLUSIONS: To increase pediatric heart transplantation in Japan, further enlightenment of the general population about pediatric organ donation is desirable.

Effect of ventricular volume before unloading in a systemic ventricle supporting the Fontan circulation.

The influence of volume overload on ventricular performance has been previously investigated but primarily with respect to the duration of overload. The aim of the present study was to elucidate whether the magnitude of the preoperative volume overload, represented by the ventricular volume, has any effect on ventricular performance long after the Fontan operation in patients with tricuspid atresia. We evaluated consecutive changes in hemodynamic catheterization data obtained at 1, 5, and 10 years after primary Fontan repair. The variables were compared between patients with larger (n = 20) and smaller (n = 21) ventricles (preoperative end-diastolic volume [percentage of predicted] 262 ± 33%, maximum 320% vs 182 ± 22%, minimum 133%, respectively). In a subgroup of patients (n = 33) who underwent symptom-limited exercise at 10.7 ± 3.0 postoperative years, the peak oxygen uptake was measured, and the potential predictors were interrogated. The difference in ventricular contractility between the groups tended to increase with time, with those with a larger ventricle showing poorer contraction, irrespective of whether it was assessed in a load-dependent (ejection fraction) or load-independent (end-systolic elastance) manner. The differences in these variables reached statistical significance at 10 years (p = 0.028 and p = 0.032). Multivariate analysis indicated a larger ventricle was an independent risk factor of poorer aerobic capacity (p = 0.047). In conclusion, ventricular performance was less preserved in those with a larger ventricle, which might result in suboptimal aerobic capacity. Our findings suggest not only early unloading, but also avoidance of excessive volume overload is of importance to minimize the deleterious effect of volume overload on an inherently susceptible ventricle.

[Peritoneal dissemination from gastrointestinal stromal tumor of small intestine responding completely to imatinib mesylate (STI 571)].

The prognosis of metastatic or recurrent GISTs is poor, because these tumors resist chemotherapy and radiotherapy. We report a patient with recurrent GIST who underwent molecularly targeted therapy with imatinib, a novel oral tyrosine kinase inhibitor. A 64-year-old man presented with large intra-abdominal mass. The patient had a history of jejunostomy with colostomy for intestinal GIST. The abdominal mass was phi3 x 3.5 cm in size with ascites at Douglas, as determined by computed tomography, and was diagnosed as a peritoneal relapse of GIST. Treatment with imatinib daily was started. After 1 month of treatment with imatinib, reduction of the abdominal tumor began to be recognized on palpation. Computed tomographic scanning at 11 months revealed that the tumor had completely disappeared. The major side effect was drug eruption,which was easily manageable with 2 weeks drug holidays. Imatinib shows promise as a safe and effective drug for the treatment of patients with recurrent GISTs.

[A case of advanced colon cancer responding completely to systemic 5-fluorouracil/l-leucovorin therapy].

A 79-year-old man was admitted for advanced transverse colon cancer with large bowel obstruction. Twelve years earlier he underwent a total gastrectomy with Roux-en Y reconstruction for gastric cancer. No metastasis was detected preoperatively. Exploratory laparotomy revealed massive direct invasion of the mesenterium of the jejunum for Roux-en Y reconstruction. The primary lesion was unresected and transverse colostomy was made. Systemic chemotherapy with 5-fluorouracil and l-leucovorin was scheduled for a total of 4 courses postoperatively. After completion of this chemotherapeutic regimen, a CT scan and colonofiberscopy revealed the primary lesions had disappeared, and a histological examination of biopsy confirmed that the patient had achieved a complete remission (CR). There was no severe side effect during chemotherapy. The patient is presently enjoying a good general condition and has been free from any sign of recurrence.

[TS-1 was prescribed for a patient with stomach cancer with peritoneal dissemination who survived for 3 years and 2 months].

A 42-year-old female patient underwent total gastrectomy for gastric cancer (Borrmann's Type 3). Many rice-grain sized peritoneal metastases were observed in the transverse colon and mesenterium. The lesion was diagnosed as stage IV cancer and the degree of radical cure was determined to be C. Chemotherapy with TS-1 was administered postoperatively. In each cycle, the drug was administered at a daily dose of 100 mg for 4 weeks, followed by a drug-free period of 2 weeks. The adverse reactions were mild, and she underwent the 2nd and further courses of therapy on an outpatient basis. Since she had acute cholecystitis during the 12th course, the drug was withdrawn for 2 months. Thereafter, the drug was started again after resolution of the cholecystitis. At present, ie, 3 years and 2 months after the surgery, the patient is receiving the 23rd course of chemotherapy on an outpatient basis, and abdominal CT shows no evidence of increase in the peritoneal metastases, enlargement of the intraperitoneal lymph nodes, or ascites.