C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci

BACKGROUND: C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion. METHODS: CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension. RESULTS: MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027). CONCLUSIONS: CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting.     

Live/real time three-dimensional transthoracic echocardiographic identification of quadricuspid aortic valve

We describe an adult in whom live/real time three-dimensional echocardiography was able to make a definite diagnosis of a quadricuspid aortic valve which was misdiagnosed as bicuspid by live two-dimensional transthoracic echocardiography (2DTTE).     

Superior vena cava, right pulmonary artery or both: real time two- and three-dimensional transthoracic contrast echocardiographic identification of the echo-free space posterior to the ascending aorta

We describe the usefulness of contrast echocardiography and live/real time three-dimensional transthoracic echocardiography in characterizing the normal structures imaged posterior to the proximal ascending aorta as superior vena cava, right pulmonary artery, or both.     

Single perforator based anterolateral thigh flap for reconstruction of large composite defects of oral cavity

Composite defects of oral cavity are a reconstructive challenge. Anterolateral thigh flap provides large and pliable tissue for reconstruction of these defects. However, wide variations in the vascular anatomy, variable perforator number and location are reported. The aim of this study was to evaluate the reliability of single perforator based large anterolateral thigh for reconstruction of complex oral cavity defects following ablative surgery. We report a series of 25 consecutive patients who underwent reconstruction of oral cavity defects with anterolateral thigh flap based on single perforator between August 2009 and August 2010. The mean flap dimension was 261cm(2) (range 80-540cm(2)). In 21 patients the flap was bi-paddled and used for inner and outer lining for cheek. None of the flaps developed perforator insufficiency. Two flaps were lost due to delayed neck wound sepsis after 7th post operative day. This study establishes safety and reliability of using a large and/or bi-paddled anterolateral thigh flap based on single perforator for reconstruction of complex oral cavity defects.