Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

Anesthetic Management of Intra-aortic Balloon Pump-Induced Systolic Anterior Motion of the Mitral Valve During Coronary Artery Bypass Grafting.

The intra-aortic balloon pump (IABP) is a mechanical device that increases myocardial oxygen perfusion and indirectly increases cardiac output through afterload reduction. Since its inception, the IABP has been a mainstay of cardiac support devices, utilized as a temporizing measure in patients with or prone to developing cardiogenic shock that are awaiting definitive treatment. Systolic anterior motion (SAM) of the mitral valve is a well-described phenomenon that can precipitate hemodynamic collapse by obstructing the left ventricular outflow tract in a subset of patients with cardiac pathology, most notably hypertrophic obstructive cardiomyopathy (HOCM). This report describes the case and anesthetic management of a patient who had an IABP placed for support and later developed SAM and hemodynamic compromise after induction of general anesthesia during a coronary artery bypass surgery.

Treatment Strategies for Hypertrophic Cardiomyopathy: Alcohol Septal Ablation and Procedural Step-by-Step Technique.

Alcohol septal ablation (ASA) is a well-established procedure for septal reduction therapy in patients with obstructive hypertrophic cardiomyopathy, significant at rest or provocable outflow tract gradients, and medically refractory symptoms. This percutaneous approach to relief of obstruction and eventual cardiac remodeling involves the infusion of a small quantity of ethanol into an appropriately targeted septal artery that is feeding the basal septum to create an iatrogenic and controlled focal infarction. Early akinesia is followed by subsequent thinning and remodeling, which widens the outflow tract, reducing or eliminating the obstruction. Historically, the use of ASA was reserved primarily for high-risk surgical candidates; however, more contemporary data suggest similar outcomes in the short-term and long-term safety of the procedure and overall effectiveness in relieving obstructive symptoms when it is performed in broader populations at experienced centers. Therefore, the current guidelines published in 2020 support ASA as a class 1 indication, similar to its open-heart surgical counterpart, surgical myectomy, when no concomitant significant coronary or valve surgical indication exists. This article summarizes contemporary management of patients with hypertrophic cardiomyopathy who were selected for ASA and details procedural methods and outcomes.

Erratum: Patient-specific fluid simulation of transcatheter mitral valve replacement in mitral annulus calcification.

[This corrects the article DOI: 10.3389/fcvm.2022.934305.].

Dynamic Left Ventricular Outflow Tract Obstruction Exacerbated by Thoracic Kyphosis.

We present a 74-year-old woman with kyphosis and symptoms of pre/syncope. Heart catheterization revealed dynamic left ventricular outflow tract obstruction (DLVOTO) with Brockenbrough Braunwald response only when kyphotic posture was assumed. She had a positive response to metoprolol. DLVOTO is a challenging diagnosis in the absence of resting LVOTO. (Level of Difficulty: Beginner.).

Can an operation provide superior outcomes for corrected transposition of the great arteries with left ventricular outflow tract obstruction? A multi-institutional study.

OBJECTIVES: Our goal was to evaluate the risk-adjusted effects of operative and non-operative repair on long-term outcomes in patients with congenitally corrected transposition of the great arteries and left ventricular outflow tract obstruction (CCTGA/LVOTO). METHODS: We retrospectively reviewed 391 patients with CCTGA/LVOTO from 2001 to 2020 (operative group, 282; non-operative group, 109) in 3 centres in China. The operative group included 73 patients who underwent anatomical repair and 209 patients who underwent non-anatomical repair. The median follow-up time was 8.5 years. The inverse probability of treatment weighted-adjusted Cox regression and a Kaplan-Meier analysis were used to evaluate long-term outcomes. RESULTS: Operative repair did not reduce the hazard ratio (HR) of death, tricuspid regurgitation or New York Heart Association functional class III/IV, but a significantly increased HR was observed for pulmonary valve regurgitation [HR, 2.84; 95% confidence interval (CI), 1.10-7.33; P = 0.031]. Compared with that in the non-operative group, anatomical repair resulted in significantly increased HRs for death (HR, 2.94; 95% CI, 1.10-7.87; P = 0.032) and pulmonary valve regurgitation (HR, 9.71; 95% CI, 3.66-25.77; P < 0.001). Subgroup analysis showed that in patients with CCTGA/LVOTO with moderate or worse tricuspid regurgitation (≥ moderate), anatomical repair significantly reduced the HR of death. An inverse probability of treatment weighting-adjusted Kaplan-Meier analysis showed that the survival rates at 5 and 10 days postoperatively were 88.2 ± 4.0% and 79.0 ± 7.9%, respectively, in the anatomical repair group; these rates were significantly lower than the rates in the non-operative group (95.4 ± 2.0% and 91.8 ± 2.8%; P = 0.032). CONCLUSIONS: For patients with CCTGA/LVOTO, operative repair does not provide superior long-term outcomes, and anatomical repair results in a higher incidence of death. However, in patients with CCTGA/LVOTO with tricuspid regurgitation ≥ moderate, anatomical repair can reduce the risk of death in the long term.

The right age for the en-bloc rotation of the outflow tracts: a single-centre experience.

OBJECTIVES: The en-bloc rotation of the outflow tracts (EBR) enables an anatomic correction of transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction. The anatomical condition or previous palliative procedures may allow choosing an elective date for the anatomic correction. The aim of this study was to evaluate the optimal age for performing the EBR based on the largest series published so far. METHODS: At the Children's Heart Center Linz, the EBR was performed in 33 patients between 2003 and 2021. Median age at operation was 74 [interquartile range (IQR) 17-627] days. Twelve patients were newborns (≤28 days), 9 older than 369 days. These 2 groups were compared to the remaining patients each regarding peri- and postoperative data, complications, reinterventions and mortality. The median follow-up period was 5.4 (IQR 0.99-11.74) years. RESULTS: In-hospital mortality was 6.1%. All-cause mortality was lower in patients younger than 369 days at the time of EBR (4.2% vs 44.4% in patients >369 days old, P = 0.013). In newborns, intensive care unit stay (median 18.5 days vs 8 days, P = 0.008) and in-hospital stay (median 29.5 days vs 15 days, P = 0.026) were significantly longer, the risk for postoperative AV block was higher (33.3 vs 0%, P = 0.012) than in patients who had been corrected anatomically after the neonatal period. CONCLUSIONS: The results of this study suggest the deferral of the EBR to the post-newborn period. A significantly higher mortality rate in patients of older age at operation seems to recommend the anatomic correction during the first year of life.

Congenitally corrected transposition with left ventricular outflow obstruction and cardiac malposition: One-and-a-half ventricular repair vs. Fontan pathway?

Objectives: This study was to assess the mid-term results of the one-and-a-half ventricular repair (hemi-Mustard and bidirectional Glenn procedures combined with the Rastelli procedure) and Fontan pathway for correcting congenitally corrected transposition of great artery (ccTGA) patients with left ventricular outflow tract obstruction (LVOTO) and cardiac malposition. Methods: In this retrospective study, 74 consecutive ccTGA with LVOTO and cardiac malposition underwent the one-and-a-half ventricular repair (group A; 33 cases) and Fontan operation (group B; 41 cases) between October 2011 and March 2018. The Median follow-up time was 49 (20-84) and 42 (7-85) months in groups A and B, respectively. To estimate excise tolerance the 6-min walk test (MWT) was performed. Results: No in-hospital death. Compared with group A, group B have significantly less CPB, mechanical ventilation time, and intensive care unit stay, but prolonged pleural effusions developed more frequently in Group B. The survival probability was 90.2% (95% CI, 80.2-100%) and 97.2% (95% CI, 92-100%) at 7 years (p = 0.300) in group A and B. The probability of freedom from re-intervention were 80.6% (95% CI, 66.5-97.6%) and 97.2% (95% CI, 92-100%) at 7 years (p = 0.110). Longitudinal repeated measured echo data at every follow-up time shows that group A has more systemic ventricular EF% (p < 0.001) and less moderate systemic ventricular valve regurgitation (p < 0.001) compared with group B. Estimated by 6 MWT, group A has better outcomes for 6-min walk distance. Conclusions: For correction of ccTGA with LVOTO and cardiac malposition, the one-and-a-half ventricular repair had superior midterm heart function and excise tolerance.

Radiofrequency Ablation for Prevention of Outflow Tract Obstruction in Percutaneous Mitral Valve-in-Valve Replacement.

Left ventricular outflow tract obstruction (LVOTO) can complicate percutaneous mitral valve replacement and may preclude patients considered high surgical risk from transcatheter therapies. We report a case of mitral valve-in-valve procedure in a patient at high risk for LVOTO. (Level of Difficulty: Advanced.).

Coincidence of Events Causing Paradoxical Hypotension in a Patient with an Intra-Aortic Balloon Pump.

The left ventricular outflow tract is a region of the left ventricle that lies between the anterior leaflet of the mitral valve and the ventricular septum. Dynamic left ventricular outflow tract obstruction (LVOTO) has classically been observed in patients with hypertrophic obstructive cardiomyopathy (HOCM) where it occurs secondary to asymmetric septal hypertrophy and systolic anterior motion (SAM) of the mitral valve. However, there are some instances that lead to hypercontractility of the myocardium, and with a combination of other physiological conditions, result in SAM of a mitral valve leaflet, leading to LVOTO in the absence of phenotype. We present such a case of an acute inferolateral wall myocardial infarction that was complicated by cardiogenic shock, requiring an intra-aortic balloon pump (IABP) and inotropic support which paradoxically provoked LVOTO. A reduction in IABP counterpulsation from 1:1 to 1:3 and the addition of intravenous fluids and a beta blocker resulted in significant improvement in blood pressure with rapid tapering of pressors. Inotropes and IABP, although helpful in cardiogenic shock, have the potential to induce or worsen the LVOTO, which can lead to a vicious cycle of worsening hypotension and increasing adrenergic drive that further deteriorates myocardial viability. Timely diagnosis with an echocardiogram and the withdrawal of inotropic and IABP support has the potential to improve haemodynamics and, thereby, outcome. LEARNING POINTS: Dynamic left ventricular outflow tract obstruction (LVOTO) should be one of the differentials in patients with cardiogenic shock, especially if it is refractory in the setting of an intra-aortic balloon pump.The diagnosis of LVOTO by echocardiography should result in immediate implementation of therapy to eliminate the factors that can potentially intensify the obstruction.

Case Report: Using Medtronic AP360 mechanical prosthesis in mitral valve replacement for patients with mitral insufficiency after primum atrial septal defect repair to reduce left ventricular outflow tract obstruction risk.

Background: Atrial septal defect is one of the most common congenital heart diseases in adults. Primum atrial septal defect (PASD) accounts for 4%-5% of congenital heart defects. Patients with PASD frequently suffer mitral insufficiency (MI), and thus, mitral valvuloplasty (MVP) or mitral valve replacement (MVR) is often required at the time of PASD repair. Unfortunately, recurrent unrepairable severe mitral regurgitation can develop in many patients undergoing PASD repair plus MVP in either short- or long-term after the repair surgery, requiring a re-do MVR. In those patients, the risk of left ventricular outflow tract obstruction (LVOTO) has increased. Case presentation: We present five such cases, ranging in age from 24 to 47 years, who had a PASD repair plus MVP or MVR for 14-40 years while suffering moderate to severe mitral regurgitation. Using Medtronic AP360 mechanical mitral prostheses, only one patient experienced mild LVOTO. Conclusions: The use of Medtronic AP360 mechanical mitral prostheses to perform MVR in patients with MI who had a history of PASD repair can potentially reduce the risk of LVOTO. Long-term follow-up is required to further confirm this clinical benefit associated with AP360 implantation in patients with PASD.

Patient-specific fluid simulation of transcatheter mitral valve replacement in mitral annulus calcification.

Introduction: Transcatheter mitral valve replacement is a promising alternative to open-heart surgery in elderly patients. Patients with severe mitral annulus calcification (MAC) are a particularly high-risk population, where postprocedural complications can have catastrophic effects. Amongst these, obstruction of the left ventricular outflow tract can lead to ventricular hypertrophic remodeling and subsequent heart failure, while subclinical valve thrombosis can result in early bioprosthetic valve failure. Methods: To elucidate the mechanisms of left ventricular outflow tract obstruction and valve thrombosis following valve-in-MAC procedures, we used image processing and Computational Fluid Dynamics (CFD) software to generate patient- and device-specific models based on preprocedural CT data. Personalized computer simulations were performed to predict the left ventricular haemodynamics after implantation in three patients with severe MAC. Results: The simulations have successfully captured the increased pressure gradient in the left ventricular outflow tract as a result of the partial obstruction due to the implanted valve. Regions of wall shear stress above the threshold value for platelet activation were also observed on the bioprosthetic frame as a result of the reduced outflow tract area, which led to increases in flow resistance and blood residence time inside the ventricle. Consistent with these findings, areas of slow recirculating flow and blood stasis formed near the valve frame, creating potential pro-thrombotic conditions. Discussion: This study provides insight into the relationship between size and shape of the outflow tract post-implantation, pressure gradients and pro-thrombotic flow metrics such as wall shear stress and blood residence time. Results show the potential of CFD modeling to bring key functional metrics into preprocedural assessment for a comprehensive evaluation of post-procedural risks beyond anatomical factors. Following further validation and extension to the atrial chamber, this approach can provide an in-depth analysis of the likelihood of valvular thrombosis.

Left Ventricular Outflow Tract Obstruction Following Transcatheter Mitral Valve Replacement Resolved by Chordal Rupture.

Transcatheter mitral valve replacement carries a risk of left ventricular outflow tract obstruction associated with mortality. We present a case of left ventricular outflow tract obstruction that resolved spontaneously when chords to the anterior mitral leaflet were found to have ruptured. (Level of Difficulty: Advanced.).

Alcohol septal ablation markedly reduces energy loss in hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: A four-dimensional flow cardiac magnetic resonance study.

BACKGROUND: Functional follow-up modalities of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) outflow tract obstruction (LVOTO) subjected to alcohol septal ablation (ASA) are limited. METHODS: This retrospective cohort study included patients of HCM with LVOTO who underwent ASA and four-dimensional (4D) flow cardiac magnetic resonance imaging (MRI) both before and after ASA. We analyzed energy loss in one cardiac cycle within the three-chamber plane of the LV and aortic root, and compared between pre- and post-ASA measurements. RESULTS: Of the 26 included patients, 10 (39%) were male, and median age was 71 (interquartile range 58-78) years. ASA significantly reduced not only LVOT pressure gradient (70 [19-50] to 9 [3-16], P < 0.001), but also energy loss during one cardiac cycle within the three-chamber plane of the LV and aortic root (80 [65-99] to 56 [45-70], P < 0.001). A linear association was observed between the reductions of energy loss and pressure gradient (R2  = 0.58, P < 0.001). CONCLUSIONS: ASA significantly reduced energy loss within the LV and aortic root as quantified by 4D flow MRI, reflecting the decreased cardiac workload. This approach is a promising candidate for serial functional follow-up in patients undergoing ASA.

Cardiogenic Shock in Obstructive Hypertrophic Cardiomyopathy Plus Apical Ballooning: Management With VA-ECMO and Myectomy.

A patient with known obstructive hypertrophic cardiomyopathy developed worsening left ventricular outflow tract obstruction, severe mitral regurgitation, and apical ballooning leading to cardiogenic shock, a combination in which treatment of each component could worsen the others. Emergency veno-arterial extracorporeal membrane oxygenation, levosimendan, and noradrenaline transiently restored adequate systemic perfusion and gas exchange. Surgical myectomy offered a more definitive solution. (Level of Difficulty: Intermediate.).

Blown Wide Open: An Unusual Case of Torrential Mitral Regurgitation Resolving With a Cough.

Mitral regurgitation can have varying hemodynamic parameters dependent on factors such as pressure gradients, exercise, and/or provocative maneuvers. We present a case of unusual dynamic mitral regurgitation resolved by coughing in a patient with hypertrophic cardiomyopathy. (Level of Difficulty: Intermediate.).