We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

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<p> It is known that high-resistance training induces morphological changes in skeletal muscle. Following a resistance training program, increases in maximum torque generating capacity are observed due to both neural adaptations and hypertrophic gains within the trained muscle. Although it has been established that a muscle hypertrophies due to the addition of myofibrillar proteins through increased protein synthesis, the exact mechanism which stimulates the hypertrophic response is unknown.</p> <p> Previous reports have shown that training in the absence of eccentric contractions generally produces less muscle growth and strength gains, as well as inflicting less damage to the muscle ultrastructure. Likewise, fast eccentric contractions have been shown to increase muscular strength to a greater extent than slow contractions. It has been hypothesized that fast eccentric contractions may maximize muscular damage, thus invoking a greater response of repair mechanisms, including satellite cell recruitment, which would allow an increased addition of contractile proteins to be added to the injured muscle, increasing muscle size and strength to a greater degree.</p> <p> The effect of fast and slow eccentric training was investigated using a bilateral, within subject model. Twelve men trained one arm fast (3.66 rad/s) and one arm slow (0.52 rad/s) for 8 weeks on an isokinetic training apparatus. Type I muscle fibre size increased with training by an average of 9.3±12.0% (P<0.05, main effect for time). Type II muscle fibres increased more in the subjects' fast trained arm when compared to the slow trained arm according to ATPase histochemical analysis (P<0.05, time x condition interaction). Likewise, whole arm cross-sectional area showed that the fast trained arms had an average increase of 6.8±5.5 % whereas the slow arms only had an average increase CSA of 5.1±5.7% (P=0.065, time x condition interaction). Maximum torque generating capacity was also increased to a greater degree (P<0.05, time x condition interaction) in the fast trained arm with an average of 10.3±16.4 Nm, whereas the slow trained arm increased only 7.3±15.0 Nm, across testing speeds. A decrease in the percentage of type IIx fibres was seen in both arms after training according to both ATPase histochemical staining and MHC gel electrophoresis; however, the percentage of type IIa fibre area increased in the fast trained arms (8.4±8.6%) more significantly (P<0.05, time x condition interaction) than the slow trained arms (1.7±10.9%).</p> <p> Seven males were trained in a similar manner to determine the extent of muscle damage which was evaluated by both Z-band streaming and force production decrements. After a single exercise bout of fast eccentric training in one arm and slow eccentric training in the other, it was determined that a 1.97±0.74 areas of moderate Z-band streaming per mm^2 of muscle in the fast exercised arm compared to 0.89±0.79 areas of moderate Z-band streaming per mm^2 of muscle in the slow trained arm (P<0.05). In conclusion, training using fast (3.66 rad/s) eccentric contractions causes a greater degree of muscle damage, hypertrophy, and strength gains than does training with slow (0.52 rad/s) eccentric contractions.</p> / Thesis / Master of Science (MSc)

Objective: We sought to determine N-terminal proatrial natriuretic peptide concentrations [Nt-proANP] in plasma from cats with hypertrophic cardiomyopathy (HCM). Secondarily, we wished to evaluate the relationship between [Nt-proANP] and echocardiographic variables. Methods: Venous blood samples were obtained from seventeen cats with HCM and from nineteen healthy cats. Plasma [Nt-proANP] was determined using an ELISA assay. The relationship between plasma [Nt-proANP] and M-mode, 2-dimensional and Doppler echocardiographic variables was evaluated. Cats that were hyperthyroid or had evidence of renal disease were excluded from the study. Results: The mean plasma [Nt-proANP] was higher in cats with HCM (3.81 +/- 1.23 pmol/l) than in control cats (3.08 +/- 1.41 pmol/l); however, this difference was not statistically significant (p=0.17). There was a significant correlation between plasma [Nt-proANP] and left ventricular posterior wall thickness (r = 0.42; p=0.01). Additionally, plasma [Nt-proANP] was correlated with left atrial size (r = 0.35; p=0.03). A linear regression model was developed to further explore these relationships. LAs2D and LVPWd had an interactive effect on plasma [Nt-proANP] (R2 = 0.2737; p= 0.02). There was no correlation between any other echocardiographic variable and plasma [Nt-proANP]. There was no correlation between plasma [Nt-proANP] and heart rate (HR), body-weight, or age. Conclusions: Cats with HCM do not have significantly higher plasma [Nt-proANP] than normal cats. There was a significant linear relationship between [Nt-proANP] and LAs2D, LVPWd and the model that described their interaction. / Master of Science

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.

Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Identifying molecular features of hypertrophic adipocytes requires appropriate in vitro models. We describe the generation of a model of human hypertrophic-like adipocytes directly comparable to normal adipose cells and the pathologic evolution toward hypertrophic state. We generate in vitro hypertrophic cells from mature adipocytes, differentiated from human mesenchymal stem cells. Combining optical, confocal, and transmission electron microscopy with mRNA/protein quantification, we characterize this cellular model, confirming specific alterations also in subcutaneous adipose tissue. Specifically, we report the generation and morphological/molecular characterization of human normal and hypertrophic-like adipocytes. The latter displays altered morphology and unbalance between canonical and dominant negative (PPARGΔ5) transcripts of PPARG, paralleled by reduced expression of PPARγ targets, including GLUT4. Furthermore, the unbalance of PPARγ isoforms associates with GLUT4 down-regulation in subcutaneous adipose tissue of individuals with overweight/obesity or impaired glucose tolerance/type 2 diabetes, but not with normal weight or glucose tolerance. In conclusion, the hypertrophic-like cells described herein are an innovative tool for studying molecular dysfunctions in hypertrophic obesity and the unbalance between PPARγ isoforms associates with down-regulation of GLUT4 and other PPARγ targets, representing a new hallmark of hypertrophic adipocytes.

Hypertrophic osteoarthropathy (HOA) is a relatively rare condition seldom diagnosed in osteoarchaeological material. In this study a skeletal material (individual 03) showing bilateral symmetric periosteal new bone formation (PNBF) was examined. Through differential diagnosis, individual 03 was considered likely to suffer from secondary HOA. The medieval urban environment that should have been contemporary with individual 03, likely permitted the spread of disease. This, together with PNBF in the ribs is thought to be indicative of underlying pulmonary disease causing the HOA. With the help of Twaddle’s theory of health and illness, individual 03 was determined to be considered ill in the last period of their life. Likely affecting their physical ability, possibly making them dependant on the care of others. When considered together with the osteological paradox, the periosteal reactions also suggests that the HOA was a complication of a chronic underlying condition. / Hypertrofisk osteoartropati (HOA) är ett relativt sällsynt tillstånd sällan diagnostiserat i det osteoarkeologiska materialet. I denna studie undersöks ett skelettmaterial benämnt individ 03 (individual03) som har bilateral symmetrisk bennybildning (PNBF). Genom differentialdiagnos bedömdesindivid 03 troligen lida av sekundär HOA. Den medeltida urbana miljö som lär ha varit samtida med individ 03, tillät troligen spridningen av sjukdomar. Detta tillsammans med PNBF på revbenen tros indikera underliggande lungsjukdom som orsak till HOA i individ 03. Med hjälp av Twaddles teori om hälsa och sjukdom blev individ 03 bedömd att bli betraktad som sjuk under den sista perioden i livet. Någonting som sannolikt påverkade fysisk förmåga, och som möjligtvis medförde beroende av vård från andra. Sedda utifrån den osteologiska paradoxen, indikerar de periostala reaktionerna att HOA i detta fall var ett resultat av en kronisk underliggande sjukdom.