Novel Strategies for Single Ventricle Management

Objective: To assess the safety and feasibility of low dose novel allogenic mesenchymal precursor cell (MPC) therapy as an adjunct to left ventricular (LV) recruitment for patients with hypoplastic left heart syndrome (HLHS) with borderline LV. In patients undergoing LV recruitment, MPC injections into the hypoplastic LV may stimulate local tissue neovascularization and LV remodeling, improving the likelihood of achieving biventricular (BiV) or 1.5 ventricle (1.5V) circulation.
Methods: Children <5 years with prior single ventricle palliation undergoing bidirectional Glenn and LV recruitment surgery (mitral valve repair, restriction) were randomized to ~20 million MPCs in ~11 injections in the LV endocardium/papillary muscles (MPC group) or standard-of-care (controls). Primary endpoint of safety was assessed at 12 months with pre-specified follow-up through 24 months for primary serious adverse events (SAEs), other adverse events (AEs), and anti-HLA panel reactive antibodies (PRA). Secondary endpoints included assessments of LV function by echocardiogram, cardiac MRI, and catheterization. Probability of BiV/1.5V conversion was estimated using Kaplan-Meier curves.
Results: 19 subjects were enrolled (15 HLHS, 4 unbalanced atrioventricular canal). Median age at LV recruitment surgery was 1.0 years (range 0.3, 3.4). 9 subjects were randomized to the MPC and 10 to the control group. 1 was lost to follow-up. There were 2 SAEs: 1 bradycardic arrest (day 8) and 1 mortality (21 months), both deemed unrelated to the trial. No cardiac tumors, intracardial hematomas or perioperative ventricular arrhythmias were detected. Median AEs per year was 1.6 for MPCs and 1.1 for controls (p=0.44). At baseline, 11/18 (61%) of patients had PRA>10% and 9/18 (50%) had PRA>90% with no difference in PRA% between groups at 12 months (Fig. 1A). In the full cohort, probability of BiV/1.5V conversion was 0.16 (95% CI: 0.05, 0.41) at 12 months and 0.54 (0.31, 0.79) at 24 months (Fig. 1B). At 12 months, LV mass, LVEDV, and LVEF on MRI were similar between the groups.
Conclusions: In a highly sensitized patient cohort undergoing LV recruitment, adjunct treatment with MPCs was safe and feasible. Over 50% underwent BiV/1.5V conversion within 2 years. Larger trials powered to detect efficacy are needed to further investigate the promising therapeutic potential of MPCs in this population. These may include dose escalation or assessment of the impact of baseline allosensitization on MPC effectiveness. 

Objective: The use of a valved Sano at the time of stage I palliation has been reported previously, but its impact on clinical outcomes needs to be further elucidated. We assessed the impact of the valved Sano compared to the non-valved Sano following stage I palliation in HLHS patients.
Methods: We retrospectively reviewed 25 consecutive HLHS neonates who underwent a valved Sano (VS) stage I operation using a femoral venous homograft and 25 consecutive HLHS neonates who underwent a standard non-valved Sano (NVS) between 2014 and 2022. Primary outcomes were ventricular function, tricuspid regurgitation, end-organ function, Sano and pulmonary artery (PA) reintervention, and survival at post-operative, discharge, interstage, and pre-Glenn time points.
Results: Perioperative characteristics and outcomes are summarized in Figure 1A. VS had a significantly lower peak lactate level (p=0.049), lactate 24 hours after peaking (p=0.02), time to diuresis (p=0.04), time to enteral feeds (p=0.02), and time to extubation (trend, p=0.08). No significant differences in mortality were seen during the hospital stay and interstage period (Fig 1A-C). The VS group had fewer patients requiring ECMO, experiencing cardiac arrest, and undergoing Sano and PA reinterventions prior to discharge following the Norwood operation (Fig 1A&B). The VS group trended towards fewer PA reinterventions overall (1 vs 7; p=0.116). Despite having worse ventricular function at baseline, the VS group showed significant improvement from the immediate post-operative period to discharge (Fig 1D arrow; p< 0.001). From preoperative to pre-Glenn time points, ventricular function within the VS was sustained, whereas ventricular function in the NVS group was significantly reduced by the time of pre-Glenn (Fig 1D; P<0.002). Pre-Glenn echocardiograms showed competent conduit valves in majority of the VS patients (n=16; 64%).
Conclusions: The VS is, or tends to be, associated with 1) improved multi-organ recovery and stability postoperatively, as demonstrated by lower lactate levels, time to diuresis, time to enteral feeds, and time to extubation; 2) increased hemodynamic stability, as exhibited by fewer patients needing ECMO or experiencing cardiac arrest postoperatively; 3) fewer PA reinterventions until stage II; and 4) augmented ventricular function recovery during stage I hospital stay. Assessment of mid- and long-term outcomes is warranted to evaluate the impact of valved Sano after stages II and III. 

Objective:
Pulmonary atresia with intact ventricular septum (PA/IVS) and right ventricular-dependent coronary circulation (RVDCC) presents unique challenges for survival due to the precarious coronary circulation. In this case we propose revascularization of the right ventricle with aortic oxygenated blood via a graft from the aorta to the hypoplastic tricuspid valve. This graft is in addition to a modified Blalock-Taussig-Thomas (mBTT) shunt to stabilize the newborn until the next procedure.

Case Video Summary:
This full-term, 4.4 kg, 3 week old neonate with PA/IVS and RVDCC was maintained on prostaglandin infusion following birth. With decrease in her pulmonary vascular resistance in her first couple of weeks of life, she had significant myocardial ischemia with ST segment changes and elevated troponin levels requiring intubation for stabilization. Heart transplantation was elected as a definitive pathway. To stabilize the precarious coronary circulation, a graft from the aorta to tricuspid valve was planned in addition to the mBTT shunt. After median sternotomy, a 3.5 mm Gore-Tex right mBTT shunt was placed between the innominate artery and right pulmonary artery off pump. A 5 mm saphenous vein homograft was sewn to the side of the ascending aorta. The distal arch and IVC were cannulated, cardiopulmonary bypass (CPB) initiated, the ductus ligated, and the heart immediately arrested in antegrade fashion to avoid myocardial ischemia given the coronary fistulas. Atrial septectomy was performed, and the saphenous vein homograft was routed into the right atrium (RA) through the RA wall and anastomosed directly to the 5 mm tricuspid valve annulus, thus intentionally making the tricuspid valve incompetent. After weaning from CPB successfully, the IVC cannula was exchanged for a Carmeda-coated cannula, and minimal left ventricular assist device (LVAD) support was initiated with PediMag at low flow of 70 ml/kg (300 ml) per minute. The patient was successfully weaned off LVAD support on postoperative day #3. She is currently still active (status 1Ae) on the transplant list.

Conclusions:
In PA/IVS with RVDCC, the use of an aortic to tricuspid graft delivers oxygenated blood to the right ventricle and avoids coronary ischemia and the need for long-term assist device support while either awaiting transplantation or the next stage in single ventricle palliation. 

Objective
Septation of a functionally univentricular heart is a largely abandoned procedure due to poor historical outcomes. Recently, there has been renewed interest in ventricular septation as an alternative to Fontan palliation in select patients.

Methods
We conducted a retrospective review of all patients with double-inlet left or right ventricle (DILV or DIRV) from 1994-2015. Those with 2 adequate atrioventricular valves (AVV) and absence of severe outlet obstruction were candidates for septation. All procedures were performed using a 1- or 2-stage strategy. In the 1-stage repair, the ventricle is divided using a non-fenestrated polytetrafluoroethylene (PTFE) patch. The 2-stage repair initially involves placement of a fenestrated PTE patch and pulmonary artery (PA) banding, then patch closure of the fenestration and PA band removal 6-12 months later.

Results
Of 103 patients with double-inlet ventricle identified during the specified period, 10 (9.7%) patients underwent attempted ventricular septation as either a planned one- (3/10, 30%) or two-stage (7/10, 70%) approach during the study period; the remainder (93/103, 90.3%) underwent single-ventricle palliation. Diagnoses included DILV (9/10, 90%) and DIRV (1/10, 10%). The 3 patients who underwent 1-stage repair were aged 3.2, 20.2, and 62.6 months; median age for 2-stage repair was 7.4 months (IQR, 4.1-10.1) at the first stage and 21.4 months (IQR, 15.5-109.4) at the second stage. One patient required a pacemaker. Of the 7 patients planned for 2-stage repair, there was 1 in-hospital mortality due to fungal sepsis, 1 patient deferred complete septation (per family preference and asymptomatic due to native PS), and 1 patient underwent Fontan after partial septation due to an unrepairable left AVV. Of the 4 patients who underwent the second stage, there were no postoperative arrhythmias or early mortality. At median follow-up of 11.0 years (range, 2.1-25.6), none underwent transplant. One patient died 8 years after complete septation from leukemia. At latest follow-up, except for one patient with moderate right AVV regurgitation, all septated patients had normal function and no more than mild AVV stenosis or regurgitation. All are NYHA functional class I.

Conclusions
Ventricular septation of the double-inlet ventricle can be performed in select patients with excellent long-term outcomes. Reconsideration of this strategy is warranted in light of the known complications of Fontan circulation.