BACKGROUND: Left ventricular outflow tract (LVOT) obstruction and paravalvular leak (PVL) are relatively uncommon, but are serious complications of prosthetic valve replacement. CASE PRESENTATION: We present a case that displays the unique therapeutic challenges of treating a patient who developed both LVOT obstruction and mitral PVL after undergoing surgical aortic and mitral valve replacement (MVR). We also describe the use of alcohol septal ablation and albumin-glutaraldehyde (BioGlue) for septal ablation to percutaneously treat the patient's LVOT obstruction, followed by use of an Amplatzer vascular plug for percutaneous closure of an antero-medial mitral PVL associated with severe regurgitation. CONCLUSION: Percutaneous interventional management of these entities may be considered as an initial therapeutic option, especially in high-risk patients with significant morbidity and mortality of repeat surgical operations.

Background: Stroke volume (SV) and aortic valve area calculations require the left ventricular (LV) outflow tract (LVOT) or aortic annular area calculations that involve squaring the respective diameters. Area calculation errors became evident with transcatheter aortic valve replacement where areas were underestimated due to an elliptical annulus. We hypothesized that LVOT and annular shape are more elliptical in patients with greater relative LV wall thickness (RWT) leading to underestimation of SV index using 2D Doppler echocardiography. Methods: We studied 203 consecutive patients referred to an outpatient noninvasive laboratory for Doppler echocardiograms which included acceptable 3-dimensional images. 3-dimensional assessment of the LVOT at 3–5 mm from the valve insertion, at the site of valve insertion, and at the sinus of Valsalva (SOV) was performed with assessment of the minor axis (MN), major axis (MJ), and areas at mid-systole. SV index was calculated from LVOT and annular diameters obtained from 2-dimensional echo and from 3-dimensional LVOT areas. Results: An inverse relation of RWT with MN/MJ at mid-systole for the LVOT (r = 0.5812, P < 0.0001) and annulus (r = 0.6865, P < 0.0001) was noted. LVOT and annulus areas were similar among groups at mid-systole. SV index calculated from 2D LVOT dimensions was significantly smaller than using 3D LVOT areas (35.6 ± 8.9 vs 53.6 ± 16.1 mL, P < 0.0001). Conclusion: There is an inverse relation between MN/MJ and RWT at the LVOT and aortic annulus despite the LVOT and annular areas being similar across most geometries resulting in SV index underestimation calculated using LVOT diameters vs 3D LVOT areas.

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<p>The two major contributing populations to the outflow tract of the heart are the secondary heart field and the cardiac neural crest. These two populations are responsible for providing the myocardium that supports the outflow tract valves, the smooth muscle that surrounds these valves and the outflow vessels themselves, and the septum that divides the primitive, single outflow tract into an aorta and pulmonary trunk. Because the morphogenesis of this region is so complex, its development is regulated by many different signaling pathways. One of these pathways is the Sonic hedgehog pathway. This thesis tests the hypothesis that Sonic hedgehog induces secondary heart field proliferation, which is necessary for normal outflow tract development. To address this hypothesis, I took advantage of small chemical antagonists and agonists to determine how too little or too much hedgehog signaling would affect the secondary heart field, both in in vitro explants and in vivo. I have determined that Sonic hedgehog signaling maintains proliferation in a subset of secondary heart field cells. This proliferation is essential for generating enough myocardium and smooth muscle and also for the cardiac neural crest to septate the outflow tract into two equal-sized vessels. Up-regulating hedgehog signaling induces proliferation, which is quickly down-regulated, showing that the embryo exhibits a great deal of plasticity. Together, these studies have shown that Sonic hedgehog promotes proliferation in a subset of the secondary heart field and that the level of proliferation must be tightly regulated in order to form a normal outflow tract.</p> / Dissertation

Background: The right ventricular outflow tract (RVOT) is known to be the origin of potentially dangerous ventricular tachycardias (VT). Arrhythmias can occur in what are otherwise assume to be structurally normal hearts as well as in arrhythmia syndromes like Brugada syndrome, catecholaminergic polymorphic VT and arrhythmogenic right ventricular dysplasia. In adults with surgically corrected tetralogy of Fallot (ToF), VT often originates in the RVOT. Methods: To investigate potential arrhythmia substrates in the structurally normal heart, the RVOT of adult rats was investigated and compared to the right ventricle (RV). In the human, the right atrium (RA), RV and the RVOT were examined in patients free of electrical and structural disease at the time of clinically indicated surgery on the left heart. The same tissue samples were collected from adults with surgically corrected ToF at the time of pulmonary valve replacement. Real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to explore changes on the mRNA level. Antibody based techniques (immunohistochemistry and Western blot) and mass spectrometry were used to identify changes on the protein level. In the rat RVOT, fine microelectrodes were employed to investigate electrophysiological characteristics. Results: A reduction in the Na+ channel Nav1.5 was found in the structurally normal RVOT in the rat and human. In the rat, RVOT-nodal like myocytes were identified. Unlike ventricular myocytes, the myocytes did not express the gap junction channel Cx43 and the K+ channel Kir2.1, but they did express the pacemaker Ca2+ channel Cav3.2 and the transcription factor Tbx3. Ectopic pacemaker and nodal-like action potentials with phase 4 depolarization were recorded from the region of the pulmonary valve. In the RA of ToF patients, SERCA2A was found to be downregulated (mRNA and protein) as seen in heart failure and atrial fibrillation. Further widespread remodelling was found in the RA, the RV and RVOT identifying multiple changes as seen in heart failure with downregulation of K+ channels and β-receptors and an increase in inflammatory markers and extracellular matrix molecules. Multiple molecules involved in the mitochondrial respiration chain were found to be downregulated in the RVOT of ToF patients. Conclusion: This is the first study that demonstrates reduction in Nav1.5 in the RVOT of structurally normal human hearts. The changes found in the rat RVOT could explain why arrhythmias originate in the RVOT. The widespread remodelling in ToF, especially in the ECM, could form a substrate for reentry arrhythmias. Mitochondrial dysfunction could point towards potential treatment targets for heart failure in this patient group.

Idiopathic ventricular tachycardias, which occur in patients without structural heart disease, are a common entity, representing up to 10% of all ventricular tachycardias evaluated by cardiac electrophysiology services. Pregnancy can increase the incidence of various cardiac arrhythmias. Factors that can potentially promote arrhythmias in pregnancy include the effects of hormones, changes in autonomic tone, hemodynamic perturbations, hypokalemia, and underlying heart disease. Ventricular arrhythmias in pregnancy are repetitive monomorphic ventricular premature complexes and couplets that frequently originate at the right ventricular outflow tract. New onset symptomatic repetitive right ventricular outflow tract ventricular tachycardia during pregnancy has been inadequately reported in the literature. We present a case of symptomatic repetitive right ventricular outflow tract tachycardia that started during pregnancy and continued in the postpartum period, requiring curative treatment with electrophysiology study and radiofrequency ablation.

Indiana University-Purdue University Indianapolis (IUPUI) / MCTP2 (multiple C2 domain transmembrane containing protein 2) encodes a protein with poorly understood roles in lipid metabolism and lipid droplet biogenesis. Genetic studies previously identified variations in MCTP2 in conjunction with left ventricular outflow tract obstructive forms of congenital heart disease (CHD). This dissertation research aimed to delineate the biomedical significance of Mctp2 by investigating its expression and consequences of its genetic deletion in mouse models. Temporal and spatial expression of Mctp2 was investigated by RT-PCR and in-situ hybridization. A novel isoform, designated as isoform 2 in mice, results from alternative pre-mRNA splicing. Similar levels of Mctp2 isoforms 1 and 2 are present in embryonic tissues, whereas isoform 1 is preferentially expressed in adult tissues with high lipid metabolism. During mouse embryonic development, in-situ hybridization suggests expression of Mctp2 at the gut tube, liver bud and near the pharyngeal arches from E8.5 – E10.5. Given association of MCTP2 with CHD, the biological significance of Mctp2 was addressed using gene trap (GT) and conditional mouse models. Survival of Mctp2 GT mice was dependent on the genetic background strain, suggesting a role for strain-specific modifiers. Conditional knockout of Mctp2 in cardiac progenitor cells displayed no effect on survival. The role of Mctp2 in cardiac development remains to be delineated. The role of Mctp2 in cardiac function was addressed in both mouse models. Initial findings suggest Mctp2 allele dosage effects on the development of heart failure. GT mice lacking one, or both, copies of Mctp2 display cardiac systolic dysfunction, with upregulation of heart failure markers at 50 weeks of age in heterozygotes and increases in cardiac fibrosis in homozygotes. Systemic conditional deletion of Mctp2 did not show heart failure phenotypes using the strain protective from lethality. However, cardiac specific deletion of Mctp2 using the Nkx2.5-Cre driver, a line that is sensitized for cardiac dysfunction, led to decreased ejection fraction and fractional shortening in mice with conditional deletion of both copies of Mctp2 as well as Mctp2 dosage dependent penetrance of cardiac dilation. These studies of knockout mice suggest a role for Mctp2 in maintenance of cardiac function and possible genetic interaction with Nkx2.5. / 2022-02-02

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