Wednesday, June 12, 2024

Single Ventricle

Background

Because hypoplastic left heart syndrome (eg, aortic atresia with mitral hypoplasia), pulmonary atresia with intact ventricular septum, and tricuspid atresia are discussed in other articles, this article considers the term “single ventricle” to apply to a double-inlet ventricle or common-inlet ventricle, two (or more, if a double-outlet atrium is also present) atrioventricular orifices, or a common atrioventricular orifice, opening into one ventricular chamber, respectively.

High-resolution analyses of early human embryonic development from Carnegie stages 13-23 (representing embryonic days 30-56)
have confirmed at least two processes that must go awry to create double-inlet left ventricle (LV): failure of the common (unseptated) atrioventricular canal to move rightward from its “starting” alignment over the eventual LV at day 30 and the contemporaneous failure to form a normal ventricular septum. These two processes may be coupled in human heart development and appear to be independent of atrioventricular canal septation itself because newborns with common-inlet LV are exceedingly rare. Common-inlet right ventricle is uncommon and occurs mostly in the setting of heterotaxy syndrome.

In a remarkable set of experiments, the developmental biologist Benoit Bruneau and his colleagues uncovered the molecular basis for ventricular septum formation.
In humans and other mammals, expression of the T-box transcription factor Tbx5 correlates with the formation of the ventricular septum (high in the left ventricle and low in the right, with a sharp boundary of expression exactly at the location where the septum forms).
The Tbx5 homozygous null mouse dies at embryonic day 10.5 with a severely hypoplastic LV
along with many other defects, reflecting the crucial role this protein has in many aspects of embryonic development.

During early development in the turtle, an animal with only one ventricle, Tbx5 is expressed throughout its lone ventricular chamber.
To prove that the level of Tbx5 is causal of ventricular septum formation rather than merely correlative, Bruneau’s laboratory genetically engineered mice to express Tbx5 at a moderate level throughout the developing heart, as in turtles, instead of the normal steep left-right gradient. Offspring from these mice had only a “single ventricle;” although left-right differences in the ventricular expression of downstream genes such as Nppa (atrial natriuretic peptide) persisted, no ventricular septum formed.

By mimicking the turtle pattern of Tbx5, these investigators had created mouse hearts that resembled turtle hearts. Therefore, a sharp line delineating an area of high expression of Tbx5 is critical to induce the formation of a ventricular septum, a precursor for the fashioning of two separate, specialized ventricular compartments. A similar single ventricle phenotype was found by Toshihiko Ogura’s laboratory when they misexpressed Tbx5 in the embryonic chick ventricle.

See the image below.

A sharp left-right gradient in Tbx5 expression is

A sharp left-right gradient in Tbx5 expression is required for the formation of the ventricular septum. Image from Zina Deretsky, National Science Foundation after Benoit Brueau, the Gladstone Institute of Cardiovascular Disease.

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Until the early 1970s, surgical management did not include separating the pulmonary and systemic circulations. Attempts to septate patients with single ventricle
were abandoned by the early 1980s because the surgically placed patch did not grow and ventricular performance remained poor. Modifications of the procedure initially proposed in 1971 by Fontan for tricuspid atresia
have been widely adopted over the last four decades. These cavopulmonary or atriopulmonary modifications effectively channel the systemic venous blood directly into the pulmonary arteries. Whether the effect on overall quality of life is superior to that of the more limited palliations used before 1971 is still unclear.

Hepatic and biliary dysfunction with possible cirrhosis, protein-losing enteropathy, and disadvantageous ejection efficiency combined with elevated after load
characterize Fontan-type circulation.
Other important sequelae include atrial tachyarrhythmias, short stature, thromboembolism, systemic venous-to-pulmonary venous collaterals, systemic artery-to-pulmonary artery collaterals, plastic bronchitis, and esophageal varices.
More detailed information about the technical aspects of the modified Fontan operation are available elsewhere.

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