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Abstract-Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg ⅐ kg], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39Ϯ0.16 mg/g) than in the cyclosporine-treated banded group (3.95Ϯ0.14 mg/g, PϽ0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02Ϯ0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6Ϯ6.1 mm Hg) and nontreatment groups (48.7Ϯ4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (Pϭ0.05) in the cyclosporine-treated banded group (4774Ϯ656 mm Hg/s) than in the nontreatment banded group (6604Ϯ516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (PϽ0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (PϽ0.05) in the cyclosporine-treated banded group (66Ϯ3.0%) than in the nontreatment banded group (79Ϯ1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure. 10 -12 Recently, Molkentin et al 10 reported that cyclosporine blocks this pathway in vitro and prevents hypertrophy in transgenic mice, in which the calcineurin pathway is enhanced. It is not clear whether this pathway is universal, ie, whether it mediates pressureoverload LVH as well as hypertrophy in transgenic models. An equally important question is whether LVH is salutary or deleterious, ie, if LVH is a beneficial compensatory mechanism, then blocking this mechanism may be deleterious and lead to decompensation and development of heart failure.Accordingly, the first goal of the present study was to determine whether cyclosporine prevents LVH due to aortic banding-induced pressure overload in mice. The second go...

Background: Arterial stiffness is used as an index of arteriosclerosis. The goal of this study was to clarify whether increased arterial stiffness, evaluated by measuring the brachial-ankle pulse wave velocity (baPWV), is a risk factor for the prognosis of heart failure (HF) patients. Methods and Results: After examination of the baPWV, as well as the levels of neurohumoral factors, the 72 enrolled HF patients were followed up for a survival study, which had a primary endpoint of re-admission because of HF. The secondary endpoint was cardiac death. Results of Cox proportional hazards modeling revealed that baPWV, systolic blood pressure (BP) and brain natriuretic peptide level were factors that affected survival (P<0.05). The patients were divided into 2 groups according to the cutoff baPWV value (1,750 cm/s). Although hemodynamic factors were similar between the groups, the high-baPWV group had a lower event-free survival rate for the primary and secondary endpoints than the low-baPWV group (P<0.05). BP at re-admission was higher in the high-baPWV group (174±30 mmHg) than in the low-baPWV group (121±33 mmHg, P<0.01). Conclusions: Elevated arterial stiffness is a risk factor for re-admission or cardiac death of HF patients. (Circ J 2009; 73: 673 -680)

Abstract-Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa ␣-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47 phox ), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-B/p65 (p-p65) in cardiomyocytes, nuclear NF-B-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, GPx3, p47 phox , collagen-I, and transforming growth factor (TGF)-␤1, the protein level of TGF-␤1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress. C -reactive protein (CRP), which is an acute-phase protein, has been regarded as a risk factor or biomarker for cardiovascular disease, including coronary artery disease, hypertension, and heart failure. Elevation of serum CRP is associated with left ventricular (LV) dysfunction and is a predictor of mortality and morbidity in patients with heart failure, independent of ischemic/nonischemic etiology and other established cardiovascular risk factors. 1-3 Laboratory evidence suggests that CRP not only serves as a biomarker but also upregulates the angiotensin type 1 receptor (AT 1 R), 4 stimulates proinflammatory cytokine production, 5 and attenuates nitric oxide (NO) production. 6 In addition, pathological examination of endomyocardial biopsies in patients with dilated cardiomyopathy revealed that CRP is frequently present in the myocardium and colocalizes with complement and macrophages. 7 Furthermore, CRP is reported to promote fibrosis and inflammation in angiotensin II-induced cardiac remodeling. 8 These findings suggest that CRP itself may play some role in the development of LV dysfunction and remodeling.Human CRP is mainly produced in the ...

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