Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice

Area of Science:

• Molecular Biology
• Cardiovascular Physiology
• Genetics

Background:

• Congenital proximal renal tubular acidosis (pRTA) is a rare genetic disorder caused by mutations in the SLC4A4 gene, affecting the NBCe1 sodium bicarbonate cotransporter.
• NBCe1 has multiple variants (NBCe1-A, -B, -C) with distinct tissue expressions; NBCe1-B is crucial for cardiac function.
• Previous studies in rats suggest NBCe1-B deficiency causes cardiac hypertrophy and prolonged QT intervals, but the effects of congenital, global NBCe1 loss on the heart remain unknown.

Purpose of the Study:

• To investigate the cardiac function in juvenile mice with congenital, global absence of NBCe1-B and NBCe1-C variants (NBCe1-B/C-null mice).
• To assess cardiac contractility, electrophysiology, and cardiomyocyte calcium handling in the absence of confounding acidemia.
• To determine the impact of congenital NBCe1-B/C deficiency on cardiac phenotype independent of systemic acidosis.

Main Methods:

• Characterization of cardiac function in NBCe1-B/C-null mice that survive up to 2 months of age.
• Assessment of cardiac hypertrophy using heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area.
• Echocardiography, intraventricular pressure-volume loop analysis, and measurement of Ca2+ transients in isolated cardiomyocytes using Fura-2 AM.

Main Results:

• NBCe1-B/C-null mice did not exhibit cardiac hypertrophy compared to controls.
• Echocardiography revealed reduced left ventricular ejection fraction, and pressure-volume measurements showed impaired load-independent cardiac contractility.
• Increased QT length variation and reduced Ca2+ transient amplitude in cardiomyocytes were observed in NBCe1-B/C-null mice.

Conclusions:

• Congenital, global absence of NBCe1-B/C variants leads to impaired cardiac contractility and increased QT length variation in juvenile mice.
• The cardiac phenotype in these mice is characterized by functional deficits rather than structural changes like hypertrophy.
• Further research is needed to elucidate the influence of neuronal and endocrine NBCe1-B/C absence on the observed cardiac phenotype.