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Cited by 66Cardiovascular Function and Risk FactorsCardiac Fibrosis and RemodelingCardiomyopathy and Myosin Studies

Transition from compensated hypertrophy to intrinsic myocardial dysfunction during development of left ventricular pressure-overload hypertrophy in conscious sheep. Systolic dysfunction precedes diastolic dysfunction

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Aoyagi, T, Fujii, A M, Flanagan, M F, Arnold, L W, Brathwaite, K W, Colan, S D, Mirsky, I·1993·Circulation
DOI 10.1161/01.cir.88.5.2415
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Abstract

BACKGROUND: Patients with aortic stenosis have a period of compensated left ventricular hypertrophy but may eventually develop congestive heart failure. Previous experimental studies showed either normal myocardial contractility in mild short-term pressure overload or myocardial dysfunction with severe pressure overload. Transition from compensated left ventricular hypertrophy to myocardial dysfunction has not been experimentally demonstrated in an adult large animal. Controversial issues in pressure-overload hypertrophy include whether the left ventricular dysfunction is due to insufficient hypertrophy (afterload mismatch) or to intrinsic myocardial dysfunction and whether diastolic dysfunction precedes systolic dysfunction. METHODS AND RESULTS: We induced left ventricular hypertrophy (41% increase in left ventricular to body weight ratio) by gradually tightening a hydraulic constrictor around the ascending aorta in 9 chronically instrumented conscious sheep. Afterload (end-systolic stress) elevation remained constant (approximately 33% greater than baseline) by adjustment of the aortic constrictor over 6 weeks, gradually increasing left ventricular pressure (from 117 +/- 6 to 163 +/- 5 mm Hg) as hypertrophy developed. Four sets (baseline, 2 weeks, 4 weeks, and 6 weeks) of serial hemodynamic studies were performed in each animal with beta-blockade, first with and then without aortic constriction to mechanically match loading conditions. Stepwise methoxamine infusion was performed to obtain load-independent assessment of myocardial contractility. Midwall shortening (P < .05) and shortening rate (P < .05) at mechanically matched loading conditions showed that myocardial dysfunction developed between the fourth and the sixth week. Shortening-preload-afterload (P < .05) and shortening rate-preload-afterload (P < .05) relations, load-independent contractility indices based on the systolic myocardial stiffness concept, also revealed depressed myocardial contractility at the sixth week. Time constant of left ventricular isovolumic relaxation and diastolic myocardial stiffness constant did not change over the 6 weeks. CONCLUSIONS: Transition from normal myocardial contractility to myocardial dysfunction was demonstrated. This transition occurred even when the elevation of afterload remained constant as hypertrophy incompletely adapted to increasing left ventricular pressure. Systolic dysfunction preceded diastolic dysfunction in this model.

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  • Various disease types can be developed in sheep, including myocardial infarction, gradual aortic constriction, and tachypacing induced heart failure.

    “Various disease types can be developed in sheep, including, but not limited to myocardial infarction (Kelley, et al., 1999; Kramer, et al., 1993), gradual aortic constriction (Aoyagi, et al., 1993; Moorjani, et al., 2003), and tachypacing induced heart failure (Byrne, et al., 2002).”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Aoyagi, et al., 1993

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Research works printed but not linked: 1

  1. Fujii AM, Vatner SF. Sympathetic mechanisms regulating myo- cardial contractility in conscious animals. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan NE, eds. The Heart and Car- diovascular System. New York: Raven Press; 1986:1119-1132.

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Authors
Aoyagi, T., Fujii, A. M., Flanagan, M. F., Arnold, L. W., Brathwaite, K. W., Colan, S. D., & Mirsky, I.
Affiliations
Brigham and Women's Hospital (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1993-11
Volume
88
Issue
5
Pages
2415-2425
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/01.cir.88.5.2415
OpenAlex
W2005110279
Cited by
66
References
35
Citations by year
2026: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2018: 1 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 4
FWCI
1.97
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (2s07rr005950-07, 5r01hl034596-05)
  • National Heart, Lung, and Blood Institute (HL 34596, HL-01452)
  • National Center for Research Resources (S07 RR-05950-05)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
left ventricular hypertrophy, pressure overload, aortic stenosis, systolic dysfunction, diastolic dysfunction, cardiac contractility, afterload mismatch, aortic constriction, sheep model, left ventricular stiffness, isovolumic relaxation, congestive heart failure
MeSH terms
Adaptation, Physiological, Animals, Diastole, Female, Heart, Cardiomegaly, Hemodynamics, Hypertension, Myocardial Contraction, Sheep, Systole, Time Factors, Ventricular Function, Left

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