Thyroid state and tolerance of mammalian myocardium to hypoxia.

Thyroid hormone is known to affect myocardial glycogen stores and thereby possibly limit anaerobic performance of mammalian cardiac muscle. Thyroid hormone administration (3,5,3'-triiodo-L-thyroxine, 300 microg/kg/day, sc) for 10 days decreased left ventricle (LV) glycogen concentration relative to euthyroid animals (2.78+/-0.46 vs. 4.28+/-0.29 mg/g of LV (mean+/-SEM)) while increasing the percent of V(1) myosin isozyme, contractile activity and cardiac mass. In contrast, thyroidectomy increased myocardial glycogen stores (8.50+/-0.56 mg/g of LV) and shifted the myosin isozyme toward V(3), prolonged contractile activity and decreased LV mass. Thyroxine administration for 3, 7 and 10 days to thyroidectomized animals progressively decreased contractile duration and increased LV mass. Thyroxine administration for 3 or 7 days to thyroidectomized rats did not reduce glycogen stores (7.75+/-1.02 and 9.62+/-1.16 mg/g of LV, respectively), whereas myocardial glycogen declined to 3.30+/-0.58 mg/g of LV after 10 days of treatment. During hypoxia, cardiac muscle from thyroidectomized rats maintained greater active force and developed less contracture relative to euthyroid and, to a greater extent, than hyperthyroid rats. Removal of glucose from the bath decreased anaerobic performance and impaired recovery; however, myocardium from thyroidectomized rats remained more tolerant to hypoxia than the euthyroid group. Overall, the intrinsic LV glycogen content was positively correlated to anaerobic performance. These data demonstrate that the thyroid state profoundly affects myocardial growth, contractility and anaerobic performance of rat myocardium. Although energy demand may affect function during hypoxia, anaerobic substrate reserve (cardiac glycogen concentration) appears to be the primary factor determining tolerance to hypoxic stress.

L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat.

BACKGROUND: The effects of long-term oral administration of L-arginine, a substrate for nitric oxide (NO) production, on left ventricular (LV) remodeling, myocardial function and the prevention of heart failure (HF) was compared to the angiotensin-converting enzyme (ACE) inhibitor captopril in a rat model of hypertensive HF (aged spontaneously hypertensive rat (SHR)). METHODS: SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats were assigned to either no treatment, treatment with L-arginine (7.5 g/l in drinking water) or captopril (1 g/l in drinking water) beginning at 14 months of age, a time when SHRs exhibit stable compensated hypertrophy with no hemodynamic impairment; animals were studied at 23 months of age or at the time of HF. RESULTS: In untreated SHR, relative to WKY, there was significant LV hypertrophy, myocardial fibrosis, and isolated LV muscle performance and response to isoproterenol (ISO) were depressed; and, 7 of 10 SHRs developed HF. Captopril administration to six SHRs attenuated hypertrophy and prevented impaired inotropic responsiveness to ISO, contractile dysfunction, fibrosis, increased passive stiffness, and HF. In contrast, L-arginine administration to SHR increased LV hypertrophy and myocardial fibrosis while cardiac performance was depressed; and 7 of 9 SHRs developed HF. In WKY, L-arginine treatment but not captopril resulted in increased LV weight and the contractile response to ISO was blunted. Neither L-arginine nor captopril treatment of WKY changed fibrosis and HF did not occur. CONCLUSION: These data demonstrate that in contrast to captopril, long-term treatment with L-arginine exacerbates age-related cardiac hypertrophy, fibrosis, and did not prevent contractile dysfunction or the development of HF in aging SHR.

Heart failure after long-term supravalvular aortic constriction in rats.

BACKGROUND: Pressure overload in humans follows a chronic and progressive course, often resulting in eventual cardiac decompensation and death. Animal models of heart failure generally fail to mimic the temporal features observed in human disease often covering a major portion of the life span, and findings of short-term studies are of uncertain applicability. The purpose was to determine whether chronic pressure overload introduced gradually in young normotensive rats would lead predictably to heart failure and to characterize specific phenotype features that have been well documented in another model of heart failure. METHODS: Rats underwent banding of the ascending aorta at 7 weeks of age such that the hemodynamic load increased gradually with ontogenic growth. Two groups of hypertrophied hearts from aortic-banded rats, with and without signs of heart failure, were compared with those of control rats at a mean age of 11 months. RESULTS: Hearts of aorta-banded rats underwent a transition from stable compensated hypertrophy to heart failure that was characterized by augmented hypertrophy, depressed contractile function, elevated fibrosis, increased myocardial stiffness, and marked alterations in the expression of genes encoding contractile, regulatory, and extracellular matrix proteins. CONCLUSIONS: Gradual constriction of the rat aorta resulted in heart failure after a variable length of time (3 to 18 months). Despite differences in genotype, the ultimate phenotype associated with the transition to failure in the aorta-banded rat is nearly identical to that observed in the aged spontaneously hypertensive rat (SHR), with a few notable differences. The findings suggest that a common heart failure phenotype follows long-term pressure overload regardless of the underlying etiology.

Studies of prevention, treatment and mechanisms of heart failure in the aging spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.