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Commentary: The hit parade

      The interplay of dominant ventricular morphology and valve regurgitation in patients with unbalanced atrioventricular septal defects is complex but may favor earlier valve repair where possible.
      See Article page 424.
      In the Venn diagram overlap of characteristics for single-ventricle candidacy, those with both unbalanced atrioventricular (AV) septal defects and significant AV valve regurgitation are among the greatest risk for palliation failure. In this issue of the Journal, King and colleagues
      • King G.
      • Buratto E.
      • Cordina R.
      • Iyengar A.
      • Grigg L.
      • Kelly A.
      • et al.
      Atrioventricular septal defect in Fontan circulation: right ventricular dominance, not valve surgery, adversely affects survival.
      present an analysis of the Australia and New Zealand Fontan Registry that attempts to tease apart the contributions of ventricular dominance (right ventricle [RV] vs left) and AV-valve surgery in this population to better profile those at greatest risk for death or transplantation. As a reflection of the existential “chicken/egg” nature of this proposition (and with all of the caveats of a retrospective registry analysis performed over several eras of operative strategy), this study highlights the interplay among RV dominance, AV-valve insufficiency, and AV-valve insufficiency of a severity to warrant repair; suffice it to say, all 3 are bad and in combination are often worse.
      Knudson's “two-hit hypothesis” was considered groundbreaking in 1971 for suggesting that most tumor suppressor genes require both alleles be inactivated to cause phenotypic transformation.
      • King G.
      • Buratto E.
      • Cordina R.
      • Iyengar A.
      • Grigg L.
      • Kelly A.
      • et al.
      Atrioventricular septal defect in Fontan circulation: right ventricular dominance, not valve surgery, adversely affects survival.
      Today, most consider this concept well beyond the Mendelian tumor syndromes it originally described and instead use it to suggest a “first hit” that more broadly provides an environment that facilitates the “second hit” in effecting full blown disease. But in the case of the patient with an unbalanced AV septal defect, which hit is which? In the study from King and colleagues,
      • King G.
      • Buratto E.
      • Cordina R.
      • Iyengar A.
      • Grigg L.
      • Kelly A.
      • et al.
      Atrioventricular septal defect in Fontan circulation: right ventricular dominance, not valve surgery, adversely affects survival.
      those with RV dominance clearly had a greater risk of mortality; they were also less likely to have had isomerism (which one might have speculated would have placed them at a survival advantage).
      • King G.
      • Buratto E.
      • Cordina R.
      • Iyengar A.
      • Grigg L.
      • Kelly A.
      • et al.
      Atrioventricular septal defect in Fontan circulation: right ventricular dominance, not valve surgery, adversely affects survival.
      In contrast, those with RV dominance more frequently had undergone a previous aortic arch reconstruction, and so who is to say it isn't a “three-hit hypothesis” (RV dominance, AV-valve regurgitation, systemic outlet obstruction) that we should be evaluating; clearly, there is more to the story.
      Despite the foundational nature of its designation to this study, the assignment of ventricular dominance and imbalance was relegated to the treating cardiologist and thus subject to the usual observational bias as apocryphally outlined by Justice Potter Stewart.

      Jacobellis V. Ohio, 378 U.S. 184 (1964) at 197 (Stewart J, concurring).

      However, laterality of imbalance appeared not to influence the development of AV-valve regurgitation, suggesting it is the existence of a common valve (and not morphology of the ventricle) that imparts much of this risk. What, then, is the biggest culprit? Is it a trifecta or a triumvirate? Lest the question seem unanswerable, we must remember that unlike mutations that lead to retinoblastoma, we have the ability to intervene on the AV valve before Fontan completion (and surgical intervention on the valve did not adversely affect the study end points).
      • Knudson Jr., A.G.
      Mutation and cancer statistical study of retinoblastoma.
      Knudson surely never intended to limit the dramatis personae to only two; indeed, as we identify more factors responsible for risk in single-ventricle disease, the hits will just keep on coming. Our ability as surgeons to intervene upon the modifiable factors—interrupt the hit parade, if you will—may be our only viable tactic to change the game.

      References

        • King G.
        • Buratto E.
        • Cordina R.
        • Iyengar A.
        • Grigg L.
        • Kelly A.
        • et al.
        Atrioventricular septal defect in Fontan circulation: right ventricular dominance, not valve surgery, adversely affects survival.
        J Thorac Cardiovasc Surg. 2023; 165: 424-433
      1. Jacobellis V. Ohio, 378 U.S. 184 (1964) at 197 (Stewart J, concurring).

        • Knudson Jr., A.G.
        Mutation and cancer statistical study of retinoblastoma.
        Proc Natl Acad Sci U S A. 1971; 68: 820-823

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