Animal models of right heart failure

Right heart failure may be the ultimate cause of death in patients with acute or chronic pulmonary hypertension (PH). As PH is often secondary to other cardiovascular diseases, the treatment goal is to target the underlying disease. We do however know, that right heart failure is an independent risk factor, and therefore, treatments that improve right heart function may improve morbidity and mortality in patients with PH. There are no therapies that directly target and support the failing right heart and translation from therapies that improve left heart failure have been unsuccessful, with the exception of mineralocorticoid receptor antagonists. To understand the underlying pathophysiology of right heart failure and to aid in the development of new treatments we need solid animal models that mimic the pathophysiology of human disease. There are several available animal models of acute and chronic PH. They range from flow induced to pressure overload induced right heart failure and have been introduced in both small and large animals. When initiating new pre-clinical or basic research studies it is key to choose the right animal model to ensure successful translation to the clinical setting. Selecting the right animal model for the right study is hence important, but may be difficult due to the plethora of different models and local availability. In this review we provide an overview of the available animal models of acute and chronic right heart failure and discuss the strengths and limitations of the different models

IN VITRO MULTI-SCALE PATIENT-SPECIFIC MODELING OF HEMODYNAMICS IN STAGE 1 NORWOOD PALLIATION FOR THE TREATMENT OF SINGLE VENTRICLE HEART DISEASE

Hypoplastic left heart syndrome (HLHS) is a congenital heart defect in which the left ventricle is severely underdeveloped. The Norwood procedure is the first stage procedure to make an unrestrictive systemic blood flow and at the same time balance it with the pulmonary flow. This is done by constructing a neo-aorta using the pulmonary artery root and the autologous aorta, and then installing a shunt to the pulmonary artery. Variations of the Norwood surgery include the modified Blalock-Taussig (mBT) shunt, which diverts blood from the innominate artery to the pulmonary artery (PA), and the Right Ventricle Shunt (RVS), which diverts blood from the right ventricle to the PA. Recurrent neo-aortic coarctation (NAO) is a frequent complication of the Norwood procedure. It causes changes in circulation flow rate balances and hypertension in the aortic arch. Conventionally, the value of a coarctation index (CoI) is used in choosing interventions to treat NAO. Aortic arch morphology of Norwood patients is suspected to be a factor of hemodynamic response to NAO. This study aims to develop and validate an in vitro model of the Norwood circulation and to use it to better understand the hemodynamic impact of progressive coarctation severity in the Norwood patients with mBT and RVS shunts. Five patient-specific cases were selected, each case having a different aortic morphology. A multi-scale mock circulatory system (MCS) was developed to simulate patient-specific Norwood circulation. The MCS couples a lumped parameter network (LPN) model of the circulation with the 3D test section of the aorta and superior arteries. The system includes branches for the pulmonary, upper body, lower body and single ventricle. The MCS was set to patient specific conditions based on the clinical measurements. Flow rate and pressure measurements were made around the circulation model. The native arch anatomy of each patient was morphed to simulate coarctation by controlling the amount of narrowing of the aortic isthmus, while keeping the original patient-specific aortic geometry intact. Separate NAO models were created to provide for a range of CoI. Aortic pressure measurements were made to study pressure drop and recovery effects. In a further study, the MCS was modified to simulate the Norwood circulation with RVS. The NAO models were used to study coarctation effects. The MCS was validated against clinical measurements. The experimental measurements demonstrated that the time-based flow rate and pressure developed within the circulation recapitulated clinical measurements (0.72 \u3c R2 \u3c 0.95). The results showed good fidelity in replicating the mean values of the Norwood circulation at the patient-specific level (p \u3e 0.10). The system demonstrated the coarctation effects in the Norwood circulation with mBT. For all patient cases, the single ventricle power (SVP), mean pressure difference, and Qp/Qs increased noticeably when CoI \u3c 0.5 (p\u3c0.05). An increased SVP correlated with abnormal aortic arch morphology (dilated or tubular). Measurements from two of four cases studied showed that substituting the mBT with the RVS can relieve pulmonary overcirculation and improve the pulmonary to systemic flow balance (Qp/Qs). Using the RVS reduced SVP requirements by 74.5 mW on average. A tubular arch morphology was associated with a higher SVP with the RVS than those patients with a dilated arch. The study has shown that the hypothesis, “NAO may not need immediate surgical intervention at an early stage for some patients†was accepted. Aortic arch morphology does affect the hemodynamic response to NAO. Any morphological abnormality causes extra SVP. The RVS can relieve overcirculation and is associated with lower SVP level and SVP changes in some of the patients

Norwood procedure with right ventricle to pulmonary artery conduit: a single-centre 20-year experience

Objectives: The aim of this study was to evaluate the long-term outcomes of the Norwood procedure with right ventricle-pulmonary artery (RV-PA) conduit for hypoplastic left heart complex (HLHC). Methods: A retrospective observational study was performed in 136 patients with HLHC who underwent a Norwood procedure with RV-PA conduit between 1998 and 2017. The probabilities of survival, reintervention and Fontan completion were analyzed. Results: Stage 1 survival was 91.9% (125/136). Reintervention for pulmonary artery stenosis was needed for 22% and 30% at stage 2 and 3, respectively, while 15% underwent reintervention for aortic arch recoarctation. Among 106 bidirectional Glenn survivors, 93 (68% of the total number of patients) had a Fontan completion, while four were not considered to be Fontan candidates. Risk factors for overall mortality included weighing Conclusions: Probabilities of survival and Fontan completion were acceptable under the current surgical strategy incorporating RV-PA Norwood procedure as the first palliation. Incorporating a strategy to maintain pulmonary artery growth and ventricular function through the staged repair is of prime importance. Further studies are necessary to observe changes in atrioventricular regurgitation as well as in right ventricular function, in patients who require atrioventricular valve interventions during the staged Fontan completion

Hemodynamic Response to Device Titration in the Shunted Single Ventricle Circulation - A Patient Cohort Modeling Study

Clinical outcomes of ventricular assist device (VAD) support for shunted single ventricle patients trail the larger population due in part to the challenges in optimizing VAD support and balancing systemic and pulmonary circulations. We sought to understand the response to VAD titration in the shunted circulation using a lumped-parameter network modeling six patient-specific clinical cases. Hemodynamic data from six patients (mean body surface area = 0.30 m2) with a systemic-to-pulmonary shunt was used to construct simulated cases of heart failure and hemodynamic response to increasing VAD flow from 5 to 10 L/min/m2. With increasing VAD flow, the pulmonary arterial pressure stayed relatively constant in five patient cases and increased in one patient case. The mean VAD flow needed to attain an arterial-venous O2 saturation difference of 30% was 6.5 ± 1.2 L/min/m2, which is higher than that in the equivalent nonshunted scenario due to the partial diversion of flow to the pulmonary circulation. The hemodynamic responses to VAD support can vary significantly between specific patient cases; therefore hemodynamic modeling may help guide an individualized approach to perioperative VAD management in the shunted single-ventricle circulation and to understand the patients who may benefit the most from VAD support

A window for reversibility in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, chronic lung disease. In patients with PAH, arteries in the lung progressively occlude and cause high pulmonary blood pressure. PAH is a fatal condition that can already present in childhood, for example in children born with a heart defect. Luckily, early diagnosis and correction of the heart defect can completely reverse PAH. But if the surgery is performed too late, the disease has lost its reversibility, the high pulmonary blood pressure will increase and cause heart failure at a young age.It is unknown why PAH loses its reversibility beyond this point of no return, and no treatment is currently available to cure irreversible PAH. In his research, Diederik van der Feen showed that arteries of rats with irreversible PAH contain high numbers of so-called senescent cells: cells that have gone into rapid-ageing and lost their normal function. These cells cannot be cleared, because they are resistant to normal programmed cell death. Accumulation of senescent cells leads to the occlusion and stiffening of the arteries, because these cells continuously excrete inflammatory factors.This research has led to two new experimental treatments, that target the disease process of PAH at different levels. Both drugs were able to reverse the occlusion of the lung vessels and could thus prevent heart failure in rats with irreversible PAH. One of these drugs is currently being tested in a clinical trial in patients with PAH

In-Vitro and In-Silico Investigations of Alternative Surgical Techniques for Single Ventricular Disease

Single ventricle (SV) anomalies account for one-fourth of all cases of congenital Heart disease. The conventional second and third stage i.e. Comprehensive stage II and Fontan procedure of the existing three-staged surgical approach serving as a palliative treatment for this anomaly, entails multiple complications and achieves a survival rate of 50%. Hence, to reduce the morbidity and mortality rate associated with the second and third stages of the existing palliative procedure, the novel alternative techniques called “Hybrid Comprehensive Stage II” (HCSII), and a “Self-powered Fontan circulation” have been proposed. The goal of this research is to conduct in-vitro investigations to validate computational and clinical findings on these proposed novel surgical techniques. The research involves the development of a benchtop study of HCSII and self-powered Fontan circulation

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients