Long-term physiological T₃ supplementation in hypertensive heart disease in rats

Abstract

Animal studies suggest that hypertension leads to cardiac tissue hypothyroidism, a condition that can by itself lead to heart failure. We have previously shown that short-term thyroid hormone treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is beneficial. This study tested the hypothesis that therapeutic, long-term T3 treatment in SHHF rats can prevent or attenuate cardiac dysfunction. Female SHHF rats were treated orally with a physiological T3 dose (0.04 μg/ml) from 12 to 24 mo of age. Age-matched female SHHF and Wistar-Kyoto rats served as hypertensive and normotensive controls, respectively. SHHF rats had reduced serum free thyroid hormone levels and cardiac tissue T3 levels, LV dysfunction, and elevated LV collagen content compared with normotensive controls. Restoration of serum and cardiac tissue thyroid hormone levels in T3-treated rats was associated with no change in heart rate, but strong trends for improvement in LV systolic function and collagen levels. For instance, end-systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels were no longer significantly different from controls. In conclusion, longstanding hypertension in rats led to chronic low serum and cardiac tissue thyroid hormone levels. Long-term treatment with low-dose T3 was safe. While cardiac dysfunction could not be completely prevented in the absence of antihypertensive treatment, T3 may offer additional benefits as an adjunct therapy with possible improvement in diastolic function.

Role Of The Thyroid System In The Dynamic Complex Network Of Cardioprotection

“…65 TH treatment with both T3 and T4 is paralleled to a reduction of the interstitial fibrosis in animal models of ischaemic and non-ischaemic HF, and this effect may be related, at least in part, to the effect of TH on MMP and TIMP activity. 66,67 T3-dependent cardiac hypertrophy was not accompanied by interstitial fibrosis but an increase of MMP-2 and TIMP-2 expression was evidenced. 67 Similarly, in rats, cardiac hypertrophy induced by T3 treatment has been associated with an increase of MMP-1 activity, a reduction of collagen I and III and a decrease in TIMP-l and 4 expression.…”

“…71,72 T3 induced angiogenesis has been documented in several experimental rat models of cardiovascular disease, including ischaemia, hypertension and diabetic cardiomyopathy. 32,66,73 In a rat model of post-ischaemic HF, T3 supplementation to correct the low T3 state favoured a better retention of capillary density in the border zone in association with HIF-1 alpha stabilisation and TR alpha 1 upregulation. 72…”

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

“…Possible crosstalk between β-adrenergic signaling and T4-induced activation of MAPK could explain this overresponse in LNCaP cells; however, this relationship seems to be complex and is not yet clear. Clinical and experimental studies have shown that chronic systolic and/or diastolic hypertension, which are associated with a high mortality risk in prostate cancer, are also accompanied by lower levels of free T4 and T3 (2,73,74). Antagonistic T3 effects on β-adrenergic signaling are consistent with the notion that synergism is lost when one of these systems is enhanced or depressed; nevertheless, meticulous studies are needed to analyze if changes in the ratio of T4/T3 could be relevant for prostate cancer progression.…”

Impact of hyperthyroidism on cardiac hypertrophy

“…In cardiac fibroblasts, although TH increase the expression of TGF-β1, a pro-fibrotic marker, TH also promote a decrease in type 1 collagen gene expression, the major fibrillar collagen in the heart (54,55,56). In fact, different studies in the literature have shown that TH induce cardiac hypertrophy without increasing collagen deposition (57,58,59).…”