The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure

M. O. Boluyt, O. H L Bing, Edward Lakatta

Research output: Contribution to journalArticle

Abstract

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to hear failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence off fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractiontal area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in β-adrenergic receptor dynamics and a shift from α- to β-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-β1 (TGF-β1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-β1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure. SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of α-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-β1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.

Original languageEnglish (US)
Pages (from-to)19-30
Number of pages12
JournalEuropean Heart Journal
Volume16
Issue numberSUPPL. N
StatePublished - 1995
Externally publishedYes

Fingerprint

Inbred SHR Rats
Hypertrophy
Heart Failure
Papillary Muscles
Muscle Cells
Transforming Growth Factors
Fibrosis
Extracellular Matrix
Myosin Heavy Chains
Captopril
Renin-Angiotensin System
Messenger RNA
Ventricular Function
Inbred WKY Rats
Hydroxyproline
Left Ventricular Function
Isoproterenol
Fibronectins
Angiotensin-Converting Enzyme Inhibitors
Adrenergic Receptors

Keywords

  • Cardiac remodelling
  • Compensated cardiac hypertrophy
  • Extracellular matrix
  • Heart failure
  • Spontaneously hypertensive rat
  • Ventricular stiffness

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. / Boluyt, M. O.; Bing, O. H L; Lakatta, Edward.

In: European Heart Journal, Vol. 16, No. SUPPL. N, 1995, p. 19-30.

Research output: Contribution to journalArticle

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