The PPARGC1A Gly482Ser polymorphism is associated with left ventricular diastolic dysfunction in men

<p>Abstract</p> <p>Background</p> <p>The Gly482Ser polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 alpha (<it>PPARGC1A</it>) has been demonstrated to be associated with diabetes, obesity and hypertension, all of which are important risk factors for left ventricular diastolic dysfunction.</p> <p>Methods</p> <p>The <it>PPARGC1A </it>Gly482Ser polymorphism was genotyped in a community-based cohort of 499 men and 533 women, who also underwent an echocardiographic examination to determine their left ventricular diastolic function. The association between the polymorphism and the presence of diastolic dysfunction was evaluated using logistic regression models.</p> <p>Results</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was significantly associated with a lower risk of diastolic dysfunction in men, but not in women. In a model adjusting for potential confounders (age, body mass index, leisure time physical activity, hypertension and diabetes) the results were still significant and substantial (odds ratio 0.13, 95% confidence interval 0.03–0.54, p for trend = 0.004). The results were consistent in a series of models, and they imply a multiplicative, protective effect of the Ser allele, with lower risk of diastolic dysfunction for each copy of the allele.</p> <p>Conclusion</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was associated with decreased risk of diastolic left ventricular dysfunction in men, but not in women, in our large community-based sample. It was associated with a substantially decreased risk, even after adjustment for potential confounders. The clinical importance of the findings has to be established in further studies.</p

Diastolic dysfunction in diabetes and the metabolic syndrome: promising potential for diagnosis and prognosis

Cardiac disease in diabetes mellitus and in the metabolic syndrome consists of both vascular and myocardial abnormalities. The latter are characterised predominantly by diastolic dysfunction, which has been difficult to evaluate in spite of its prevalence. While traditional Doppler echocardiographic parameters enable only semiquantitative assessment of diastolic function and cannot reliably distinguish perturbations in loading conditions from altered diastolic functions, new technologies enable detailed quantification of global and regional diastolic function. The most readily available technique for the quantification of subclinical diastolic dysfunction is tissue Doppler imaging, which has been integrated into routine contemporary clinical practice, whereas cine magnetic resonance imaging (CMR) remains a promising complementary research tool for investigating the molecular mechanisms of the disease. Diastolic function is reported to vary linearly with age in normal persons, decreasing by 0.16 cm/s each year. Diastolic function in diabetes and the metabolic syndrome is determined by cardiovascular risk factors that alter myocardial stiffness and myocardial energy availability/bioenergetics. The latter is corroborated by the improvement in diastolic function with improvement in metabolic control of diabetes by specific medical therapy or lifestyle modification. Accordingly, diastolic dysfunction reflects the structural and metabolic milieu in the myocardium, and may allow targeted therapeutic interventions to modulate cardiac metabolism to prevent heart failure in insulin resistance and diabetes

Disturbances in myocardial diastolic and vascular function with the emphasis on type 2 diabetes : Diagnostic and therapeutic opportunities

Background and aims Cardiovascular involvement is common in diabetes and diastolic myocardial and endothelial dysfunction are early signs. The prognosis is serious and tools for early detection and a search for improved management strategies are important. This thesis explores tools for the early detection of myocardial involvement and examines whether intensive glucose control could improve diastolic and endothelial dysfunction in patients with type 2 diabetes mellitus. Study I In comparison with mitral pulse wave Doppler, Tissue Doppler Imaging (TDI), a relatively pre-load independent technique, may improve the early identification of patients with diastolic dysfunction. Fifteen controls without heart failure, 30 patients with heart failure, were studied, 15 patients with diastolic left ventricular dysfunction and 15 with systolic left ventricular dysfunction. All the patients with diastolic heart failure were identified by mitral pulse wave Doppler or TDI, but only 11 were identified by atrio-ventricular plane displacement. The number of false positive patients were eight, ten and nine, respectively (p<0.01, p<0.05 and NS) for each of the three methods. Study II Eighty-seven patients with type 2 diabetes classified as having no (n=60), mild (n=13) or moderate (n=14) left ventricular diastolic dysfunction by Doppler echocardiography and TDI were investigated with Velocity Vector Imaging (VVI) which evaluates myocardial deformation (strain). Left atrial volume was larger in patients with moderate diastolic dysfunction compared with mild or no diastolic dysfunction (p=0.01). Left atrial roof strain distinguished no diastolic dysfunction from mild and moderate diastolic dysfunction (p=0.0073). Systolic left atrial strain correlated to total emptying fraction (r=0.70, p<0.0001) and inversely to left atrial volume (r=-0.35, p=0.0009). Studies III-IV Thirty-nine patients with type 2 diabetes and signs of diastolic dysfunction but no other cardiovascular disease manifestations were randomly assigned to glucose normalisation by insulin (I-group; n=21) or oral glucose-lowering agents (O-group; n=18). Myocardial diastolic dysfunction and coronary flow reserve were studied with Doppler echocardiography, including TDI and myocardial contrast-enhanced echocardiography. Fasting glucose and HbA1c were normalised in both groups, but this did not significantly influence myocardial diastolic dysfunction in either group (p=0.65). There was no difference in coronary flow reserve before and after improved glycaemic control. Twenty-two of the patients (I-group n=10; O-group n=12) were also investigated in terms of endothelial function and skin microcirculation by brachial artery flowmediated dilatation (FMD) and laser Doppler fluxmetry respectively. Glycaemic normalisation did not improve microcirculation. A reduction in FMD from 6.0 ± 2.2 to 4.7 ± 3.0% was observed in the I-group (p=0.037), but there was no change in the O-group (4.3±2.3 to 4.7±3.3%; p=0.76). The between-group difference was not significant (p=0.12). Conclusions TDI is useful for diagnosing diastolic myocardial dysfunction, with accuracy similar to that of conventional echocardiography including mitral pulse wave Doppler flow. Left atrial deformation, measured as regional and overall systolic strain, is impaired in patients with type 2 diabetes mellitus and mild to moderate left ventricular diastolic dysfunction and offers new information on regional LA function and LA volumes. Further, it may add to traditional Doppler echocardiography measurements for diagnosis of diastolic dysfunction. The hypothesis that improved glycaemic control would reverse early signs of myocardial diastolic and endothelial dysfunction in patients with type 2 diabetes was not proven. Whether it is possible to influence more pronounced dysfunction, particularly in patients with less well-controlled and long-standing diabetes, remains to be further explored in controlled clinical trials