Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis.

BACKGROUND: Rheumatic heart disease is the major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to rheumatic heart disease, but greater insight into their roles in disease progression is needed. METHODS: We used a Cdh5-driven EC lineage-tracing approach to identify and track ECs in the K/B.g7 model of autoimmune valvular carditis. Single-cell RNA sequencing was used to characterize the EC populations in control and inflamed mitral valves. Immunostaining and conventional histology were used to evaluate lineage tracing and validate single-cell RNA-sequencing findings. The effects of VEGFR3 (vascular endothelial growth factor receptor 3) and VEGF-C (vascular endothelial growth factor C) inhibitors were tested in vivo. The functional impact of mitral valve disease in the K/B.g7 mouse was evaluated using echocardiography. Finally, to translate our findings, we analyzed valves from human patients with rheumatic heart disease undergoing mitral valve replacements. RESULTS: Lineage tracing in K/B.g7 mice revealed new capillary lymphatic vessels arising from valve surface ECs during the progression of disease in K/B.g7 mice. Unsupervised clustering of mitral valve single-cell RNA-sequencing data revealed novel lymphatic valve ECs that express a transcriptional profile distinct from other valve EC populations including the recently identified PROX1 (Prospero homeobox protein 1)+ lymphatic valve ECs. During disease progression, these newly identified lymphatic valve ECs expand and upregulate a profibrotic transcriptional profile. Inhibiting VEGFR3 through multiple approaches prevented expansion of this mitral valve lymphatic network. Echocardiography demonstrated that K/B.g7 mice have left ventricular dysfunction and mitral valve stenosis. Valve lymphatic density increased with age in K/B.g7 mice and correlated with worsened ventricular dysfunction. Importantly, human rheumatic valves contained similar lymphatics in greater numbers than nonrheumatic controls. CONCLUSIONS: These studies reveal a novel mode of inflammation-associated, VEGFR3-dependent postnatal lymphangiogenesis in murine autoimmune valvular carditis, with similarities to human rheumatic heart disease.

Statistical shape representation of the thoracic aorta: accounting for major branches of the aortic arch.

Statistical shape modeling (SSM) is an emerging tool for risk assessment of thoracic aortic aneurysm. However, the head branches of the aortic arch are often excluded in SSM. We introduced an SSM strategy based on principal component analysis that accounts for aortic branches and applied it to a set of patient scans. Computational fluid dynamics were performed on the reconstructed geometries to identify the extent to which branch model accuracy affects the calculated wall shear stress (WSS) and pressure. Surface-averaged and location-specific values of pressure did not change significantly, but local WSS error was high near branches when inaccurately modeled.

New-onset postoperative atrial fibrillation after mitral valve surgery: Determinants and the effect on survival.

Objective: Mitral valve surgery (MVS) carries substantial risk of postoperative atrial fibrillation (PAF). Identifying patients who benefit from prophylactic left atrial appendage amputation (LAAA) or maze is ill-defined. To guide such interventions, we determined preoperative predictors of PAF and investigated 3-year survival of patients with PAF. Methods: We performed a retrospective analysis of patients undergoing isolated MVS (N = 670) between 2011 and 2021. Patients with preoperative atrial fibrillation, LAAA or pulmonary vein isolation were excluded. Patient characteristics were compared between those without PAF and those who developed transient or prolonged PAF. Predictors of any PAF and prolonged PAF were identified using multivariable regression analysis. Results: In total, 504 patients without preoperative atrial fibrillation underwent isolated MVS. Of them, 303 patients (60.2%) developed PAF; 138 (27.3%) developed transient and 165 (32.7%) developed prolonged (beyond 30 days) PAF. Patients with PAF were older (65.7 vs 54.3 years, P < .001), with larger left atria (4.8 vs 4.3 cm, P < .001), greater prevalence of hypertension (60% vs 47.8%, P < .05), and were New York Heart Association class III/IV (36% vs 8.5%, P < .001). Independent predictors of PAF included left atria volume index (odds ratio [OR], 1.02; P < .003), older age (OR, 1.04; P < .001), heart failure (OR, 6.73; P < .001), and sternotomy (OR, 2.19; P < .002). Age, heart failure, and sternotomy were independent predictors of prolonged PAF. Patients with PAF had greater mortality at 3 years compared with those without PAF (5.3% vs 0.5%, P < .005). On multivariable analysis, PAF was associated with increased mortality (hazard ratio, 7.81; P < .046). Conclusions: PAF is common after MVS and associated with late mortality. Older age, advanced heart failure, and sternotomy are associated with prolonged PAF. These factors may identify patients who would benefit from prophylactic LAAA or ablation during MVS.

Aortic valve repair for isolated right coronary leaflet prolapse.

Objectives: Isolated right coronary leaflet prolapse is a common cause of nonaneurysmal aortic insufficiency, but can rarely occur in patients with proximal aortic aneurysms. Standardized techniques for routine autologous repair of this disorder are presented. Methods: Most aortic valve leaflet prolapse is isolated to the right coronary leaflet, with hypertension and annular dilatation being contributory. Echocardiographically, a posteriorly eccentric aortic insufficiency jet together with "fracture" of the right leaflet tip are diagnostic. Primary repair includes internal geometric ring annuloplasty to downsize and reshape the annulus, together with central plication of the prolapsing leaflet. Thickened, scarred, or retracted noduli are released using an ultrasonic aspirator. The goal is to achieve equivalent coaptation heights of ≥8 mm for all 3 leaflets. Results: Three videos of 6 cases are provided to illustrate these techniques. In the first, 3 patients are shown with classic isolated right leaflet prolapse. In the second and third videos, alternative pathologies are presented for contrast. Applying the reconstructive approaches of geometric ring annuloplasty, leaflet plication, and ultrasonic nodular release, excellent early and late repair outcomes are obtainable in most patients. Conclusions: The combination of aortic ring annuloplasty, central leaflet plication, and ultrasonic nodular release allows routine and standardized repair of right coronary leaflet prolapse, either isolated or concomitant with aneurysm surgery.

Fifty Percent Reduction in Narcotic Use After Minimally Invasive Cardiac Surgery Using Liposomal Bupivacaine.

OBJECTIVE: Minimally invasive cardiac surgery via a right minithoracotomy (RMT) is a common approach to different valve pathologies, tumor resection, and atrial septal defect (ASD) closure. We studied intraoperative field block using liposomal bupivacaine (LB) in these operations. METHODS: Consecutive 171 minimally invasive RMTs (fourth intercostal space) were studied, and patients in cardiogenic or septic shock, intravenous drug abuse, and those re-explored were excluded (n = 12). An early cohort was treated with standard postoperative analgesia while another underwent intraoperative field block with LB immediately after incision. We compared postoperative pain level, narcotic utilization (morphine milligram equivalent), and intensive care unit (ICU) and hospital length of stay. RESULTS: The procedures included 48 isolated mitral valve replacements (MVR); 2 MVR with other procedures; 93 mitral valve repairs (MVRr); 9 MVRr with other procedures; 4 isolated tricuspid valve repairs; 2 myxoma resections; 1 ASD closure. There were 13 patients in the non-LB group and 146 patients in the LB group. Use of LB decreased mean postoperative narcotic utilization by 50% (P = 0.003). The LB group had lower pain levels on postoperative day 1 (P = 0.039), which continued through postoperative day 5 (P = 0.030). We found no difference in ICU or hospital length of stay between groups. There were no complications from LB field block. CONCLUSIONS: LB field block decreases postoperative pain and narcotic utilization after cardiac surgery via a RMT, but it does not reduce length of stay. The technique is safe and should be considered in all patients undergoing RMT cardiac surgery.

A Simple Porcine Model of Inducible Sustained Atrial Fibrillation.

The surgical management of atrial fibrillation (AF) is an evolving field with a history of testing various lesion sets and ablation technologies. Previous animal models of AF require a chronic intervention to make AF reliably inducible. Our objective was to create an acute, reliable, and reproducible porcine model of sustained AF. To accomplish this, 21 adult domestic pigs underwent median sternotomy. Methods to induce AF were then performed sequentially: manual stimulation, rapid pacing (200 beats per minute), and then rapid pacing of 8 beats with a cycle length of 300 milliseconds, followed by an extra stimulus at decreasing cycle lengths. If AF was not induced, burst pacing was performed at a cycle length of 90 milliseconds for 30 seconds. If AF was still not induced, intravenous neostigmine was administered, and the process was repeated. Atrial fibrillation was considered sustained after 1 minute. Attempts at AF induction were successful in 18 (86%) of 21. Atrial fibrillation was induced during manual stimulation in four (19%), during rapid pacing in five (24%), during burst pacing in five (24%), and after the administration of neostigmine in four (19%). Mean (SD) duration of AF was 3.6 (2.6) minutes. Of the 18, 14 (78%) reverted to sinus rhythm spontaneously and 4 (22%) required an antiarrhythmic. This technique of inducing AF can easily be used to evaluate new technologies and lesion sets without the need for creating a chronic animal model.

Quantification of the functional consequences of atrial fibrillation and surgical ablation on the left atrium using cardiac magnetic resonance imaging.

OBJECTIVES: The effect of atrial fibrillation (AF) on left atrial (LA) function has not been well defined and has been largely based on limited echocardiographic evaluation. This study examined the effect of AF and a subsequent Cox-Maze IV (CMIV) procedure on atrial function. METHODS: Cardiac magnetic resonance imaging (cMRI) was performed in 20 healthy volunteers, 8 patients with paroxysmal atrial fibrillation (PAF) and 7 patients with persistent or long-standing persistent atrial fibrillation (LSP AF). Six of the PAF patients underwent surgical ablation with the CMIV procedure and 5 underwent both pre- and postoperative cMRIs. The persistent or LSP AF patients underwent only postoperative cMRIs because all scans were performed with patients in normal sinus rhythm. Volume-time curves throughout the cardiac cycle and regional wall shortening were evaluated using the cine images and compared across groups. RESULTS: Compared with normal volunteers, patients with PAF had significantly decreased reservoir contribution to left ventricular (LV) filling (P = 0.0010), an increased conduit function contribution (P = 0.04) and preserved booster pump function (P = 0.14). Following the CMIV procedure, significant reductions were noted with respect to reservoir and booster pump function, with corresponding increases in conduit function. These differences were more drastic in patients with persistent/LSP AF. Regional wall motion was significantly reduced by PAF in all wall segments (P < 0.05), but was not further reduced by the CMIV. Despite changes in LA function, LV function was preserved following surgery. CONCLUSIONS: PAF significantly altered LA function and has a detrimental effect on regional wall motion. Surgical intervention further altered LA function, but the reasons for this are likely multifactorial and not entirely related to the lesion set itself.

The cat as a model for human obesity: insights into depot-specific inflammation associated with feline obesity.

According to human research, the location of fat accumulation seems to play an important role in the induction of obesity-related inflammatory complications. To evaluate whether an inflammatory response to obesity depends on adipose tissue location, adipokine gene expression, presence of immune cells and adipocyte cell size of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were compared between lean and obese cats. Additionally, the present study proposes the cat as a model for human obesity and highlights the importance of animal models for human research. A total of ten chronically obese and ten lean control cats were included in the present study. Body weight, body condition score and body composition were determined. T-lymphocyte, B-lymphocyte, macrophage concentrations and adipocyte cell size were measured in adipose tissue at different locations. Serum leptin concentration and the mRNA expression of leptin and adiponectin, monocyte chemoattractant protein-1, chemoligand-5, IL-8, TNF-alpha, interferon-gamma, IL-6 and IL-10 were measured in blood and adipose tissues (abdominal and inguinal SAT, and omental, bladder and renal VAT). Feline obesity was characterised by increased adipocyte cell size and altered adipokine gene expression, in favour of pro-inflammatory cytokines and chemokines. Consequently, concentration of T-lymphocytes was increased in the adipose tissue of obese cats. Alteration of adipose tissue was location dependent in both lean and obese cats. Moreover, the observed changes were more prominent in SAT compared with VAT.

Proliferation capacity of T-lymphocytes is affected transiently after a long-term weight gain in Beagle dogs.

Across species obesity is associated with several disorders but in companion animals little information is available on the impact of chronic obesity on immune competence. The aim of the present study was to investigate whether weight gain and stable obese bodyweight affects the immune cell response. Obesity was induced in eight adult healthy beagle dogs (weight gain group; WGG) by a weight gain period (WGP) of 47 weeks, which was immediately followed by a period (stable period: SP) of stable obesity of 26 weeks. Eight adult healthy beagle dogs were included as a control group (CG) and remained at their ideal bodyweight throughout the entire study. Body composition was measured at five intervening time-points. Concentration of serum leptin and inflammatory cytokines, functionality of lymphocytes and phagocytic activity of neutrophils and monocytes were evaluated at ten intervening time-points. Serum leptin concentration was rising during the WGP in the WGG but went to lower concentrations during the SP. At the end of long-term weight gain, a decreased mitogen-induced proliferation of T-lymphocytes was noted but this alteration seemed to be transient after stabilization of bodyweight. This finding may imply an altered immune response for dogs with different energy balances. However, no systemic low grade inflammation or alteration in other immune cell functions was observed. Consequently it is suggested that the change in energy balance during the onset of obesity (becoming obese versus being obese), evokes an additional obesity-related disorder in dogs, i.e. impaired T-lymphocyte immune function.

Trends in the indications and survival in pediatric heart transplants: a 24-year single-center experience in 307 patients.

BACKGROUND: Heart transplantation is the only viable treatment for children with end-stage heart failure due to congenital heart disease (CHD) or cardiomyopathy. This study reviewed the trends in the indications for transplant and survival after transplant during the past 24 years. METHODS: A retrospective review was performed of the 307 heart transplants performed at our center since 1986. To analyze the trends in the indications for transplant as well as operative death and late-survival, the data were divided into three periods in 8-year increments: 1986 to 1993 (50 patients), 1994 to 2001 (116 patients), and 2002 to 2009 (141 patients). RESULTS: The indications for transplantation were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 173 with CHD, 139 (80%) had single-ventricle (SV) anomalies. In the CHD group, transplantation for failed SV palliation, including Fontan procedure, became the predominant indication in the last 8-year interval of our program. Survival after transplant was the best in patients with cardiomyopathy and the worst in patients with failed palliations for SV anomalies, including failed Fontan procedures. CONCLUSIONS: Transplantation for heart failure related to failed SV palliation has become the most common indication for patients with CHD. The high-risk nature of these transplants will have significant implications for heart transplant programs as more infants with SV anomalies survive palliative procedures performed during infancy.

Differential modulation of right ventricular strain and right atrial mechanics in mild vs. severe pressure overload.

Increased right atrial (RA) and ventricular (RV) chamber volumes are a late maladaptive response to chronic pulmonary hypertension. The purpose of the current investigation was to characterize the early compensatory changes that occur in the right heart during chronic RV pressure overload before the development of chamber dilation. Magnetic resonance imaging with radiofrequency tissue tagging was performed on dogs at baseline and after 10 wk of pulmonary artery banding to yield either mild RV pressure overload (36% rise in RV pressure; n = 5) or severe overload (250% rise in RV pressure; n = 4). The RV free wall was divided into three segments within a midventricular plane, and circumferential myocardial strain was calculated for each segment, the septum, and the left ventricle. Chamber volumes were calculated from stacked MRI images, and RA mechanics were characterized by calculating the RA reservoir, conduit, and pump contribution to RV filling. With mild RV overload, there were no changes in RV strain or RA function. With severe RV overload, RV circumferential strain diminished by 62% anterior (P = 0.04), 42% inferior (P = 0.03), and 50% in the septum (P = 0.02), with no change in the left ventricle (P = 0.12). RV filling became more dependent on RA conduit function, which increased from 30 ± 9 to 43 ± 13% (P = 0.01), than on RA reservoir function, which decreased from 47 ± 6 to 33 ± 4% (P = 0.04), with no change in RA pump function (P = 0.94). RA and RV volumes and RV ejection fraction were unchanged from baseline during either mild (P > 0.10) or severe RV pressure overload (P > 0.53). In response to severe RV pressure overload, RV myocardial strain is segmentally diminished and RV filling becomes more dependent on RA conduit rather than reservoir function. These compensatory mechanisms of the right heart occur early in chronic RV pressure overload before chamber dilation develops.

Performance of a novel dual-electrode bipolar radiofrequency ablation device: a chronic porcine study.

OBJECTIVE: : Over recent years, a variety of energy sources, including bipolar radiofrequency, have been used to replace the traditional incisions of the Cox-Maze procedure for the surgical treatment of atrial fibrillation (AF). The purpose of this study was to evaluate the safety and efficacy of a novel dual-electrode bipolar radiofrequency ablation device Synergy (Atricure, Inc., Cincinnati, OH USA) for AF in a chronic porcine model. METHODS: : Six domestic pigs underwent a modified Cox-Maze IV procedure without cardiopulmonary bypass using the Synergy device. Animals survived for 30 days. Each pig then underwent induction of AF and was killed to remove the heart en bloc for histologic assessment. Each ablation line was dissected perpendicularly at 5-mm intervals to assess the lesion width, depth, and transmurality. RESULTS: : All animals survived the operation. Electrical isolation of the left atrial appendage and the pulmonary veins were documented by pacing acutely and at 30 days after the operation in all six animals. All animals failed to be induced in AF at 30 days. There was no gross evidence of intra-atrial thrombus formation or stricture of the pulmonary veins. All ablations (n = 209) examined were discrete, linear, and transmural, with a mean lesion width of 3.0 ± 0.7 mm and a mean lesion depth of 5.4 ± 3.3 mm. The mean ablation time was 16.3 ± 4.4 seconds, with a mean total energy delivery of 238 ± 170 J. CONCLUSIONS: : The Atricure Synergy was able to create reliable chronic transmural lesions of the modified Cox-Maze IV procedure on a porcine beating heart without cardiopulmonary bypass. The ablation lines were significantly wider when compared with its predecessor, the Isolator II.

Efficacy of a novel bipolar radiofrequency ablation device on the beating heart for atrial fibrillation ablation: a long-term porcine study.

OBJECTIVE: Over recent years, a variety of energy sources have been used to replace the traditional incisions of the Cox maze procedure for the surgical treatment of atrial fibrillation. This study evaluated the safety and efficacy of a new bipolar radiofrequency ablation device for atrial ablation in a long-term porcine model. METHODS: Six pigs underwent a Cox maze IV procedure on a beating heart off cardiopulmonary bypass using the AtriCure Isolator II bipolar ablation device (AtriCure, Inc, Cincinnati, Ohio). In addition, 6 pigs underwent median sternotomy and pericardiotomy alone to serve as a control group. All animals were allowed to survive for 30 days. Each pig underwent induction of atrial fibrillation and was then humanely killed to remove the heart en bloc for histologic assessment. Magnetic resonance imaging scans were also obtained preoperatively and postoperatively to assess atrial and ventricular function, pulmonary vein anatomy, valve function, and coronary artery patency. RESULTS: All animals survived the operation. Electrical isolation of the left atrial appendage and the pulmonary veins was documented by pacing acutely and at 30 days in all animals. No animal that underwent the Cox maze IV procedure was able to be induced into atrial fibrillation at 30 days postoperatively, compared with all the sham animals. All 257 ablations examined were discrete, linear, and transmural, with a mean lesion width of 2.2 +/- 1.1 mm and a mean lesion depth of 5.3 +/- 3.0 mm. CONCLUSIONS: The AtriCure Isolator II device was able to create reliable long-term transmural lesions of the modified Cox maze procedure on a beating heart without cardiopulmonary bypass 100% of the time. There were no discernible effects on ventricular or valvular function.

Animal studies of epicardial atrial ablation.

The Cox maze procedure is an effective treatment of atrial fibrillation, with a long-term freedom from recurrence greater than 90%. The original procedure was highly invasive and required cardiopulmonary bypass. Modifications of the procedure that eliminate the need for cardiopulmonary bypass have been proposed, including use of alternative energy sources to replace cut-and-sew lesions with lines of ablation made from the epicardium on the beating heart. This has been challenging because atrial wall muscle thickness is extremely variable, and the muscle can be covered with an epicardial layer of fat. Moreover, the circulating intracavitary blood acts as a potential heat sink, making transmural lesions difficult to obtain. In this report, we summarize the use of nine different unidirectional devices (four radiofrequency, two microwave, two lasers, one cryothermic) for creating continuous transmural lines of ablation from the atrial epicardium in a porcine model. We define a unidirectional device as one in which all the energy is applied by a single transducer on a single heart surface. The maximum penetration of any device was 8.3 mm. All devices except one, the AtriCure Isolator pen, failed to penetrate 2 mm in some nontransmural sections. Future development of unidirectional energy sources should be directed at increasing the maximum depth and the consistency of penetration.

Impact of calcium-channel blockers on right heart function in a controlled model of chronic pulmonary hypertension.

BACKGROUND AND OBJECTIVE: Patients with chronic pulmonary hypertension (CPH) who demonstrate pulmonary vasodilation following calcium-channel blocker (CCB) administration are defined as 'responders'. In contrast, 'nonresponders' are patients who do not show such pulmonary vasodilation with CCB therapy. The purpose of this investigation was to study the effects of CCB therapy on right heart mechanics in experimental CCB responders versus CCB nonresponders. METHODS: In 12 dogs, right atrial (RA) and ventricular pressure and volume (conductance catheters) were simultaneously recorded after 3 months of progressive pulmonary artery banding. Diltiazem was given at 10 mg h with the pulmonary artery constricted (simulated CCB nonresponder). Responders were then created by releasing the pulmonary artery band to unload the ventricle. RA and right ventricular contractility and diastolic stiffness (slope of end-systolic and end-diastolic pressure-volume relations) were calculated and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed compared with open, respectively. RESULTS: With CCB, RA contractility (P < 0.03) and cardiac output (P < 0.004) were compromised in simulated nonresponders whereas RA stroke work was pharmacologically depressed in the setting of an unchanged afterload. After simulating a responder by controlled pulmonary artery band release, the right atrium became less distensible, causing a shift from reservoir to conduit function (P < 0.001) towards physiological baseline conditions and a recovery in the hyperdynamic compensatory response in both chambers (P < 0.007) as evidenced by declined RA and right ventricular contractility with an improved cardiac output as compared with CPH and simulated nonresponders. RA and right ventricular diastolic function in both groups was not affected by CCB. CONCLUSION: CCB did not affect right ventricular function in simulated nonresponders but significantly impaired RA contractility and cardiac output. In simulated responders, afterload fell substantially, thereby allowing the right atrium and right ventricle to recover from their pathological hyperdynamic contractile response to CPH. This effect outweighed the intrinsic negative effects of CCB therapy on systolic RA function. Current data suggest that the right atrium in CPH is much more sensitive to CCB therapy than the right ventricle and show for the first time why CCB therapy in CPH has been empirically restricted to documented responders.

Interatrial shunt for chronic pulmonary hypertension: differential impact of low-flow vs. high-flow shunting.

The purpose of the present study was to determine for the first time the qualitative and quantitative impact of varying degrees of interatrial shunting on right heart dynamics and systemic perfusion in subjects with chronic pulmonary hypertension (CPH). Eight dogs underwent 3 mo of progressive pulmonary artery banding, following which right atrial and ventricular end-systolic and end-diastolic pressure-volume relations were calculated using conductance catheters. An 8-mm shunt prosthesis was inserted between the superior vena cava and left atrium, yielding a controlled model of atrial septostomy. Data were obtained 1) preshunt or "CPH"; 2) "Low-Flow" shunt; and 3) "High-Flow" shunt (occluding superior vena cava forcing all flow through the shunt). With progressive shunting, right ventricular pressure fell from 72 +/- 19 mmHg (CPH) to 54 +/- 17 mmHg (Low-Flow) and 47 +/- 17 mmHg (High-Flow) (P < 0.001). Cardiac output increased from 1.5 +/- 0.3 l/min at CPH to 1.8 +/- 0.4 l/min at Low-Flow (286 +/- 105 ml/min, 15% of cardiac output; P < 0.001), but returned to 1.6 +/- 0.3 l/min at High-Flow (466 +/- 172 ml/min, 29% of cardiac output; P = 0.008 vs. Low-Flow, P = 0.21 vs. CPH). There was a modest rise in systemic oxygen delivery from 252 +/- 46 ml/min at CPH to 276 +/- 50 ml/min at Low-Flow (P = 0.07), but substantial fall to 222 +/- 50 ml/min at High-Flow (P = 0.005 vs. CPH, P < 0.001 vs. Low-Flow). With progressive shunting, bichamber contractility did not change (P = 0.98), but the slope of the right atrial end-diastolic pressure volume relation decreased (P < 0.04), consistent with improved compliance. This study demonstrated that Low-Flow interatrial shunting consistently improved right atrial mechanics and systemic perfusion in subjects with CPH, while High-Flow exceeded an "ideal shunt fraction".