Differential cardiac remodeling in preload versus afterload.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cardiac Remodeling

Background:

• Hemodynamic load is a key regulator of myocardial function and gene expression.
• The distinct effects of afterload and preload on cardiac phenotype remain incompletely understood.
• This study investigates differential cardiac responses to pressure (afterload) and volume (preload) overload.

Purpose of the Study:

• To test the hypothesis that afterload and preload, despite similar average load, result in different cardiac phenotypes.
• To elucidate the molecular mechanisms underlying these distinct phenotypes.
• To identify potential targets for pharmacological intervention.

Main Methods:

• Comparison of transverse aortic constriction (TAC) for afterload and aortocaval shunt (shunt) for preload in mice.
• Assessment of cardiac structure, function, and molecular signaling at various time points post-surgery.
• Analysis of gene and microRNA expression profiles.

Main Results:

• Both TAC and shunt models increased cardiac load, but with distinct patterns of wall stress.
• TAC induced maladaptive fibrotic hypertrophy with increased calcium/calmodulin-dependent protein kinase II (CaMKII) signaling, altered calcium cycling, inflammation, and apoptosis.
• Shunt induced hypertrophy with Akt activation, but without significant fibrosis or apoptosis, and better preserved cardiac function.
• TAC mice exhibited higher mortality and reduced fractional shortening compared to shunt mice at 8 weeks.

Conclusions:

• Afterload (TAC) leads to maladaptive cardiac remodeling characterized by fibrosis, apoptosis, and CaMKII-dependent calcium handling abnormalities.
• Preload (shunt) is associated with adaptive hypertrophy, Akt activation, and better functional outcomes with lower mortality.
• Distinct hemodynamic loads induce unique cardiac phenotypes, necessitating tailored pharmacological strategies for treatment.