Although familial hypertrophic cardiomyopathy (FHC) is characterized as cardiac 
disease in the absence of overt stressors, disease penetrance, and pathological 
progression largely depend on modifying factors. Accordingly, pressure overload 
by transverse aortic constriction (TAC) was induced in 2-month-old, male mice 
with and without a FHC (R403Q) mutation in α-myosin heavy chain. A significantly 
greater number of FHC mice (n = 8) than wild-type (WT) mice (n = 5) died during 
the 9-week study period. TAC induced a significant increase in cardiac mass 
whether measured at 2 or 9 weeks post-TAC in both WT and FHC mice, albeit to a 
different extent. However, the temporal and morphological trajectory of 
ventricular remodeling was impacted by the FHC transgene. Both WT and FHC hearts 
responded to TAC with an early (2 weeks post-TAC) and significant augmentation 
of the relative wall thickness (RWT) indicative of concentric hypertrophy. By 9 
weeks post-TAC, RWT decreased in WT hearts (eccentric hypertrophy) but remained 
elevated in FHC hearts. WT hearts following TAC demonstrated enhanced cardiac 
function as measured by the end-systolic pressure-volume relationship, pre-load 
recruitable stroke work (PRSW), and myocardial relaxation indicative of 
compensatory hypertrophy. Similarly, TAC induced differential histological and 
cellular remodeling; TAC reduced expression of the sarcoplasmic reticulum 
Ca(2+)-ATPase (2a) (SERCA2a; 2 and 9 weeks) and phospholamban (PLN; 2 weeks) but 
increased PLN phosphorylation (2 weeks) and β-myosin heavy chain (β-MyHC; 9 
weeks) in WT hearts. FHC-TAC hearts showed increased β-MyHC (2 and 9 weeks) and 
a late (9 weeks) decrease in PLN expression concomitant with a significant 
increase in PLN phosphorylation. We conclude that FHC hearts respond to TAC 
induced pressure overload with increased premature death, severe concentric 
hypertrophy, and a differential ability to undergo morphological, functional, or 
cellular remodeling compared to WT hearts.