Abstract-Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including ␣-and ␤-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) ␤1, ␣1, and ␣2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid-and hyperthyroid-like changes in the TH target genes, ␣-and ␤-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TR␤1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TR␤1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TR␤1 to transcription of ␤-MyHC, SERCA, and TR␤1, and TR␣1 to ␣-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy. (Circ Res. 2001;89:591-598.) Key Words: thyroid hormone receptor Ⅲ physiological and pathological hypertrophy Ⅲ ␣ 1 -adrenergic receptor Ⅲ cardiac myocyte Ⅲ rat C ardiac hypertrophy is sometimes considered a single process that leads invariably to myocardial dysfunction (pathological hypertrophy). However, physiological hypertrophy exists in which cardiac function is maintained or enhanced, including normal cardiac development, exercise training, and thyroid hormone (TH) treatment. Exercise and TH can reverse molecular and functional abnormalities in pathological hypertrophy without decreasing ventricular mass, indicating that physiological and pathological hypertrophy are qualitatively distinct processes. [1][2][3][4][5][6] TH-responsive genes in cardiac muscle include ␣-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA), which are induced by TH, and ␤-MyHC, which is repressed. 7,8 An intriguing observation is that pathological hypertrophy is characterized by hypothyroid-like changes in these target genes, with decreases in ␣-MyHC and SERCA and increases in ␤-MyHC, a molecular phenotype also called the fetal program. 9 The fact that TH treatment can reverse these genetic changes in some models of pathological hypertrophy is additional evidence for a hypothyroid state, but TH blood levels are usually normal. 3 Conversely, physiological hypertrophy caused by exercise is characterized ...

Background-Calcineurin may play a pivotal role in the signaling of cardiac hypertrophy; since this hypothesis was first put forward, controversial reports have been published using various experimental models. . Treatment with cyclosporin A completely inhibited the development of LVH in EX rats, but it only partially attenuated the development of LVH in AC4 rats. Conclusions-Calcineurin was activated in exercise-induced physiological LVH and in the developing phase of LVH (AC1), but not in decompensated pressure-overload hypertrophy (AC4). Cyclosporin therapy for the prevention of LVH may be harmful because it does not block the development of pathological hypertrophy but rather that of favorable adaptive hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARγ and that expression can be augmented over time in mitogen-activated splenocytes. PPARγ ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARγ ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARγ is expressed in both murine CD4 and CD8 cells and that PPARγ ligands directly decrease IFN-γ expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARγ antagonist, increases lymphocyte IFN-γ expression. Transient transfection studies reveal that PPARγ ligands, in a PPARγ-dependent manner, potently repress an IFN-γ promoter construct. Repression localizes to the distal conserved sequence of the IFN-γ promoter. Our studies also demonstrate that PPARγ acts on the IFN-γ promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARγ ligands may be related to direct inhibition of IFN-γ by PPARγ.

PETCO2 was below normal in cardiac patients at rest and during exercise. PETCO2 was correlated with exercise capacity and cardiac output during exercise, and the sensitivity and specificity of PETCO2 regarding decreased cardiac output were good. PETCO2 may be a new ventilatory abnormality marker that reflects impaired cardiac output response to exercise in cardiac patients diagnosed with heart failure.

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t has been suggested that exercise training improves the cardiac output response to exercise in patients with previous myocardial infarction, 1 but individual evaluation has been limited partly because of the invasiveness and difficulties inherent in the method used to measure cardiac output. If the response of cardiac output during exercise could be estimated noninvasively, it would be of practical use in evaluating the therapeutic effects of training in patients with various heart diseases.End-tidal CO2 pressure (PETCO2) is a noninvasive index obtained from respiratory gas monitoring. Variations in PETCO2 have been shown to reflect changes in cardiac output and pulmonary blood flow in animals and humans under constant ventilation. 2-9 It has been reported that PETCO2 is influenced by changes of heart rate (presumably cardiac output) in patients with a pacemaker. 10 Compared with normal subjects, patients with a pulmonary embolism have a low PETCO2, probably because of increased physiological dead space attributable to decreased pulmonary blood flow. 11 It has also been shown that patients with cardiac disease have an abnormally low PETCO2 during exercise, especially those with an impaired response of cardiac output during exercise 12 or with decreased peak oxygen uptake (V • O2). 13 Taking all these findings together, PETCO2 might be a good estimate of cardiac output in cardiac patients over a wide range of conditions. In the present study, we measured PETCO2 and cardiac output during exercise in patients undergoing aerobic training started early after the onset of acute myocardial infarction (AMI). Methods Study PatientsThirty-six patients (35 men, 1 woman) were randomly assigned to either a training group (n=18) or a control group (n=18) 1 week after the onset of AMI. The 13 patients (70 %) in the training group and 12 patients (67 %) in the control group underwent successful percutaneous coronary intervention before entering the study. There were Background End-tidal CO2 partial pressure (PETCO2) has been suggested as a noninvasive index reflecting cardiac output under constant ventilation. The aim of this study was to examine whether PETCO2 does reflect cardiac output, even during exercise, in patients with acute myocardial infarction (AMI) undergoing exercise training early after onset. Method and ResultsPatients aged 47-73 years were randomly assigned to either a training group (n=18) or a control group (n=18) 1 week after the onset of AMI. Those in the training group performed exercise training under supervision at the anaerobic threshold level for 2 weeks, while patients in the control group followed a conventional walking regimen. In the training group, but not in the control group, PETCO2 at the respiratory compensation point increased significantly from 39.1±3.5 to 41.1±3.7 mmHg (p<0.01). Similarly, the cardiac index at peak exercise increased only in the training group (from 6.04±0.98 to 7.31±0.97 L/min per m 2 , p<0.01). These 2 measurements correlated well both before and after the study period. ...

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