Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor.

Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC, Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin-deficient (Nrdc-/- ) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild-type mice is denser in the subepicardium than in the subendocardium, Nrdc-/- LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full-length form of p75 neurotrophin receptor (p75NTR , Ngfr) is increased in Nrdc-/- LV due to the reduced ectodomain shedding of p75NTR . Importantly, the reduction of p75NTR rescued the abnormal innervation phenotype of Nrdc-/- mice. Moreover, sympathetic neuron-specific, but not cardiomyocyte-specific deletion of Nrdc recapitulated the abnormal innervation patterning of Nrdc-/- mice. In conclusion, neuronal nardilysin critically regulates cardiac sympathetic innervation and circulatory dynamics via modulation of p75NTR .

Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts.

Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.

Analysis of liver metabolism in a rat model of heart failure.

BACKGROUND: Cachexia, namely body wasting, is a common complication in cases of congestive heart failure (CHF). Although, neurohumoral and immune abnormalities are associated with the condition, precisely how the imbalance of catabolism and anabolism is responsible for the wasting process is not known. METHODS: We analyzed markers of cachexia in Dahl salt-sensitive rats which show marked hypertension with preserved systolic function at 11 weeks and CHF at 17-19 weeks of age. We also analyzed the change in hepatic metabolism associated with CHF since liver plays a central role in the systemic regulation of catabolism and anabolism. RESULTS: In CHF rats, a failure to grow was observed and blood hepatic protein levels were decreased associated with increased blood proinflammatory cytokine levels, indicating that Dahl rats serve as a model of cardiac cachexia. Food intake was reduced, and blood sugar and insulin levels were decreased. Despite the apparent fasting condition, blood fatty acid levels were decreased and triglycerides levels were increased. In CHF rats, liver incorporated more glucose, the gene expression related to gluconeogenesis was decreased, the gene expression related to lipogenesis was increased, and the triglyceride content of the liver was increased. The paradoxical production of triglycerides synthesis in fasting rats was associated with a proinflammatory response in liver. CONCLUSIONS: The Dahl salt-sensitive rat can be used as a model of cardiac cachexia. The cachexia was associated with abnormal hepatic metabolism that might work as a maladaptive response during the progression of CHF.

Kidney function and histological damage in autopsy subjects with myocardial infarction.

OBJECTIVES: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD). We previously reported renal parenchymal damage in autopsy subjects with stroke or abdominal aortic aneurysm. The aim of this study is to evaluate the relationship between renal histology and clinical characteristics of patients with myocardial infarction (MI). METHODS: A total of 699 subjects were autopsied at the National Cerebral and Cardiovascular Center Hospital. We retrospectively evaluated all autopsy cases with MI (n = 123). Estimated glomerular filtration rate (eGFR) was calculated using the Japanese formula. Subjects were classified into four groups: 25 subjects with eGFR ≥ 60 mL/min/1.73 m(2) and no proteinuria (no CKD), 10 subjects with eGFR ≥ 60 and proteinuria (CKD1/2), 65 subjects with 60 > eGFR ≥ 30 (CKD3), and 23 subjects with eGFR < 30 (CKD4/5). Renal parenchymal damage was evaluated using a semi-quantitative histological score (score 0-3) for glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and arteriosclerosis of medium-sized artery (maximum score = 15). RESULTS: The mean histological score was significantly higher in patients with CKD3 and CKD4/5 and was associated with age, hypertension, diabetes, kidney function, proteinuria, and other CVD. CONCLUSIONS: In patients with MI, renal parenchymal damage and deteriorating kidney function are closely associated.

The cutoff value of aldosterone-to-renin ratio for the diagnosis of primary aldosteronism in patients taking antihypertensive medicine.

BACKGROUND: Primary aldosteronism (PA) may account for as much as 6-20% of cases of refractory hypertension referred to hypertension clinics. Because antihypertensive agents affect the physiologic renin-angiotensin-aldosterone system, screening diagnostic tests for PA are generally performed after antihypertensive agents are discontinued. However, such tests can be dangerous for patients with severe hypertension or other cardiovascular complications. However, a reliable cutoff value for the aldosterone-to-renin ratio (ARR) has not been established, especially for Asians, including the Japanese. METHOD: Fifty-five consecutive patients with clinically suspected PA were evaluated from July 10, 2001, to March 1, 2005, at the National Cardiovascular Center in Japan. Every referred patient was screened prospectively for PA with the ARR at the outpatient clinic. The patients tested continued to be treated with a variety of antihypertensive agents. We reviewed the sensitivity, specificity, and accuracy of the ARR without modifying the antihypertensive agents. The diagnosis of PA was established with the results of both abdominal computed tomography and adrenal scintigraphy. RESULTS: Of the 55 patients, 27 were found to have PA, including adrenal adenoma (n = 18) and bilateral adrenal hyperplasia (n = 9). The mean ARR of patients with PA was significantly higher than that of patients without PA. By assuming a cutoff value of the ARR >or= 69 calculated from the receiver operating characteristics curve, the highest sensitivity (81%), specificity (82%), positive-predictive value (81%), and negative-predictive value (81%) were obtained. CONCLUSION: The data suggest that an ARR >or= 69 strongly indicates PA in Japanese patients with hypertension being treated with antihypertensive agents.

A case of neurally mediated syncope induced by laughter successfully treated with combination of propranolol and midodrine.

A 69-year-old man had been suffering from recurrent syncope induced by laughter since the age of 58. His syncope was reproduced by head-up tilt testing with isoproterenol infusion and we concluded that his laughter-induced syncope was one type of neurally mediated syndrome (NMS). His daughter also had NMS and her syncope was treated with propranolol. Propranolol and midodrine hydrochloride, an alpha(1)-adrenergic stimulant, were effective at preventing his laughter-induced syncope. This is a case report of laughter-induced syncope with a familial predisposition successfully treated with the combination of the nonselective beta-blocker propranolol and the alpha(1)-stimulator midodrine.

Asymptomatic renal infarction, due to fibromuscular dysplasia, in a young woman with 11 years of follow-up.

We report a 27-year-old woman with renovascular hypertension, renal infarction, and hepatic artery aneurysm due to fibromuscular dysplasia. The patient was first noted to have renal artery aneurysm and hepatic artery aneurysm at the age of 17. The renal infarction was asymptomatic and was incidentally detected by magnetic resonance imaging (MRI) examination. Because of the rather peripheral location of the aneurysms, percutaneous transluminal renal artery angioplasty was considered inappropriate. This case suggests the need for long-term and periodical follow-up of patients with fibromuscular dysplasia.