Right ventricular dysfunction in hypoplastic left heart syndrome: superimposed effects of afterload and insulin resistance in puberty?
Year: 2022
Type: editorial
Abstract: We read with interest the article by Sobh et al. [1], which showed moderate increases in indexed right ventricular (RV) volumes and slight decreases in RV ejection fraction and long-axis strain in patients with hypoplastic left heart syndrome (HLHS) following Fontan completion. Longitudinal data in late childhood and adolescence are exceedingly rare in this population, so the authors should be commended on their important contribution. A finding that particularly stood out in their study was that statistically significant increases in indexed RV volume were observed only in patients older than 10 years at their latest examination. One explanation could be that RV dysfunction remains compensated for a time, but after 10 years RV dilation begins to manifest. It is intriguing that indexed RV end-diastolic and end-systolic volumes remain stable from the first to the second examination (median age 4.2 and 9.4 years, respectively) and then increase remarkably at the third examination (median age 14.5 years). This particular timing suggests the possibility that physiological changes associated with puberty may have promoted RV deterioration. The well-known association between age and increasing blood pressure is especially prominent around puberty and at least in part may account for the timing of RV dilation in HLHS [2]. Particularly poorly suited for work against high afterloads, the RV and tricuspid valve may fail when they encounter the normal pubescent rise in blood pressure. The onset of significant tricuspid regurgitation may account for the disproportionate prominence of RV volume changes relative to changes in ejection fraction and strain. A recent study by Liu et al. [3] suggests another possible mechanism. In 25 patients with cyanotic congenital heart disease, they found that transition to puberty was associated with a shift from glucose to lipid metabolism in conjunction with a decrease in left ventricular ejection fraction. Further animal experiments revealed that insulin resistance during puberty suppressed myocardial hypoxia-inducible factor 1-α resulting in metabolic dysregulation and myocardial dysfunction. When insulin resistance was relieved with the insulin sensitizer pioglitazone, these effects were reversed and contractility was restored. While Liu et al. [3] included patients with various types of cyanotic congenital heart disease, chronic hypoxia is central to the pathophysiology of HLHS [4]. Furthermore, Liu et al. [3] primarily focused on the LV yet similar effects of insulin resistance on RV dysfunction have been established [5]. Collectively, there are several implications of these findings: (i) patients with HLHS may experience a superimposed (‘acute-on-chronic’) deterioration in RV function during puberty, which may be either transient or irreversible; (ii) afterload reduction may deserve another serious evaluation for its potential to delay or prevent RV dysfunction in HLHS; and (iii) insulin resistance may represent a promising therapeutic target to further improve outcomes of these patients and protect them against the ‘hit’ of puberty. Before any definitive answer can be provided, we need studies with longitudinal follow-up extending beyond adolescence into adulthood. This underscores the shared conviction in the congenital cardiac community that future research efforts should embrace a lifespan perspective on CHD [6]. Sobh et al. [1] make a great initial step in this direction. Conflict of interest: Shelby Kutty is a consultant for GE Healthcare and OP2 Drugs. All other authors declare that they have no competing interests.
Institutions: Johns Hopkins University, Johns Hopkins Hospital, KU Leuven
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4210810860