Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis

Perforin gene (PRF1) mutations cause the primary form of hemophagocytic lymphohistiocytosis (HLH). We report a genetic defect of PRF1 in a 62-year-old Japanese man with recurrent episodes of HLH. Sequencing of PRF1 from both peripheral blood mononuclear cells and nail clippings showed compound heterozygous mutation, including deletion of two base pairs at codons 1090 and 1091 (1090-1091delCT) and guanine-to-adenine conversion at nucleotide position 916 (916GAEA). Although primary HLH has been detected in infants and children, genetic mutation of PRF1 or other genes should be considered a differential diagnosis of HLH even in the elderly.     

Nicorandil promotes myocardial capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats

Long-term administration of vasodilators increases shear stress, which is thought to be important for vascular growth in the heart. Nicorandil, an activator of ATP-sensitive potassium channels with a nitrate-like action, is a potent vasodilator. We have now investigated the effects of nicorandil on vascular growth and gene expression in the failing heart of Dahl salt-sensitive (DS) hypertensive rats. DS rats fed a high-salt diet from 6 weeks of age develop concentric cardiac hypertrophy secondary to hypertension at 11 weeks, followed by heart failure at 18 weeks. DS rats on such a diet were treated with a nonantihypertensive oral dose of nicorandil (6 mg/kg per day) or vehicle from 11 to 18 weeks of age. Treatment of DS rats with nicorandil improved cardiac function and attenuated the development of heart failure. Myocardial capillary and arteriolar densities did not differ between vehicle-treated DS rats and age-matched controls. The abundance of mRNAs for endothelial NO synthase (eNOS), vascular endothelial growth factor (VEGF), the VEGF receptor Flt-1, and basic fibroblast growth factor (bFGF) in the myocardium was markedly reduced in vehicle-treated DS rats compared with controls. Treatment of DS rats with nicorandil greatly increased capillary and arteriolar densities and inhibited the downregulation of eNOS, VEGF, fms-like tyrosin kinase-1, and bFGF gene expression. This, nicorandil stimulates coronary capillary and arteriolar growth and thereby likely suppresses the development of heart failure in DS rats. Nicorandil may prove beneficial for the treatment of hypertensive heart failure as well as of ischemic heart disease.     

Clinical significance of high-sensitivity C-reactive protein in lifestyle-related disease and metabolic syndrome

OBJECTIVES: High-sensitivity C-reactive protein (hs-CRP), a biochemical marker of subclinical inflammation, is associated with atherosclerosis and cardiovascular disease. The present study evaluated the clinical usefulness of hs-CRP in lifestyle-related diseases and metabolic syndrome. METHODS: Hs-CRP was measured in 407 subjects who underwent a checkup at our Medical Office of Cardiology. Levels of hs-CRP were compared between various clinical conditions associated with lifestyle-related diseases and metabolic syndrome. RESULTS: Levels of hs-CRP were significantly high in the subjects with hypertension, hyperlipidemia, diabetes, obesity, and metabolic syndrome (p < 0.001). Both diabetes and metabolic syndrome were strongly associated with hs-CRP levels (diabetes: p = 0.0001, beta = 0.184; metabolic syndrome: p < 0.00001, beta = 0.264). In addition, hs-CRP levels were strongly associated with number of risk factors, and hs-CRP levels were significantly increased with increased number of risk factors. In patients with many risk factors, levels of hs-CRP were significantly higher in subjects with abdominal obesity than in normal subjects (p < 0.001). Waist circumference and hemoglobin A1c levels represented independent predictors for hs-CRP levels in subjects with metabolic syndrome (waist circumference: p < 0.00001, beta = 0.256; hemoglobin A1c: p < 0.00001, beta = 0.242). CONCLUSIONS: Levels of hs-CRP were strongly associated with lifestyle-related diseases, metabolic syndrome, and increased number of risk factors. These results suggest that measurement of hs-CRP may be useful in risk management for clinical practice.