MYOCARDIAL FIBROSIS AND STIFFNESS WITH HYPERTROPHY AND HEART-FAILURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

Background Fibrosis is commonly found in association with cardiac hype rtrophy and failure, but the relation of the connective tissue respons e to the development of impaired cardiac function remains unclear. We examined passive myocardial stiffness, active contractile function, an d fibrosis in the spontaneously hypertensive rat (SHR), a model of chr onic pressure overload in which impaired cardiac function follows a lo ng period of stable hypertrophy. Methods and Results We studied the pa ssive and active mechanical properties of left ventricular (LV) papill ary muscles isolated from normotensive Wistar-Kyoto (WKY) rats and spo ntaneously hypertensive rats (SHR) at the ages of 12 months and 20 to 23 months. Seven of 15 SHR between 20 and 23 months of age had finding s consistent with heart failure (SHR-F). In comparison to preparations from WKY rats and nonfailing SHR (SHR-NF), papillary muscles from the SHR-F group demonstrated increased passive stiffness (central segment exponential stiffness constant, k(cs): SHR-F 95.6+/-19.8, SHR-NF 42.1 +/-9.7, WKY rats 39.5+/-9.5 (mean+/-SD); SHR-F P<.01 versus SHR-NF, WK Y rats). The increase in stiffness was associated with an increase in LV collagen concentration (SHR-F 8.71+/-3.14, SHR-NF 5.83+/-1.20, WKY rats 4.78+/-0.70 mg hydroxyproline/g dry LV wt; SHR-F P<.01 versus SHR -NF, WKY rats); an increase in interstitial fibrosis, as determined hi stologically (SHR-F 13.5+/-8.0%, SHR-NF 4.9+/-2.1%, WKY rats 3.6+/-0.8 %; SHR-F P<.01 versus SHR-NF, WKY rats); and impaired tension developm ent (SHR-F 3.18+/-1.27, SHR-NF 4.41+/-1.04, WKY rats 4.64+/-0.85 kdyne /mm(2); SHR-F P<.05 versus SHR-NF; P<.01 versus WKY rats). Conclusions The development of heart failure in the aging SHR is associated with marked myocardial fibrosis, increased passive stiffness, and impaired contractile function relative to age-matched nonfailing SHR and nonhyp ertensive control animals. These data suggest that fibrosis or events underlying the connective tissue response are important in the transit ion from compensated hypertrophy to failure in the SHR.