Lesley Donelan

Effect of preload reduction by haemodialysis on new indices of diastolic function.

Assessment of mitral annular motion diastolic velocities by M-mode or tissue Doppler imaging and the propagation velocity of early diastolic filling (Vp) by colour M-mode have been proposed as preload-independent indices of diastolic function. The aim of the present study was to determine the effects of preload reduction by haemodialysis on these new echocardiographic indices and to assess the relationship between these indices. The study group comprised 17 patients with chronic renal failure in sinus rhythm with normal left ventricular systolic function who underwent echocardiography 30 min prior to and 30 min following haemodialysis. Following dialysis there were significant reductions in weight (P<0.001), left atrial diameter (P=0.001), the peak Doppler velocity of early diastolic transmitral flow (P=0.005) and the ratio of Doppler velocities of early to late diastolic transmitral flow (P=0.02), consistent with a reduction in intravascular volume. There was no change after dialysis in early diastolic mitral annular velocity using M-mode (P=0.19) or tissue Doppler imaging from either the septal or lateral walls (P=0.88 and P=0.15 respectively), but there was a reduction in Vp after dialysis (55 to 49 cm/s; P=0.04). There were only weak correlations between Vp and the early diastolic mitral annular velocities (r<0.6 for all). We conclude that the assessment of diastolic function by the mitral annular early diastolic velocity appears to be preload-independent, that Vp may be affected by preload and that there is only a weak relationship between Vp and the early diastolic mitral annular velocity.

Early Changes in Left Ventricular Long-Axis Function in Friedreich Ataxia: Relation with the FXN Gene Mutation and Cardiac Structural Change

OBJECTIVE Friedreich ataxia (FRDA) is an autosomal recessive condition due to a GAA triplet expansion in the FXN gene that causes increased left ventricular (LV) wall thickness and can progress to LV systolic dysfunction. However, the changes in myocardial function that occur before a reduction in LV ejection fraction are incompletely understood. METHODS LV long-axis function was assessed by measurement of tissue Doppler imaging (TDI) peak systolic (S`), early diastolic (E`), and atrial velocities (A`) at the septal and lateral borders of the mitral annulus in 60 subjects homozygous for a GAA expansion in the FXN gene who had preserved LV ejection fraction. Comparison was made with 60 sex- and age-matched controls. TDI velocities at 5 years were compared with baseline values in 17 FRDA subjects with follow-up studies who still had preserved ejection fraction. RESULTS S` and E` were reduced in FRDA subjects at both the septal and the lateral mitral annular borders. Lateral E` was independently and inversely related to age, blood pressure, septal wall thickness, and the number of GAA repeats in the smaller allele of the FXN gene, whereas septal E` was not correlated with GAA repeat number. At 5 years, there was a reduction in lateral S` and E` but no change in septal TDI velocities. CONCLUSION Subjects with FRDA have impairment of septal and lateral long-axis LV function, but there also seem to be regional differences in the effects of this condition that are at least partly related to the degree of genetic abnormality.

A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition with a heterogeneous cardiac phenotype caused primarily by an expanded GAA trinucleotide repeat in the frataxin gene (FXN). FXN is important in mitochondrial iron efflux, sensitivity to oxidative stress, and cell death. The number of GAA repeats on the smaller FXN allele (GAA1) only accounts for a portion of the observed variability in cardiac phenotype. Genetic modifying factors, such as single nucleotide polymorphisms (SNPs) in genes of the Renin-Angiotensin-Aldosterone system (RAAS), may contribute to phenotype variability. This study investigated genetic variability in the angiotensin-II type-1 receptor (AGTR1), angiotensin-converting enzyme (ACE), and ACE2 genes as cardiac phenotype modifying factors in FRDA patients. Comprehensive review of the AGTR1, ACE and ACE2 genes identified twelve haplotype tagging SNPs. Correlation of these SNPs with left ventricular internal diameter in diastole (LVIDd), interventricular septal wall thickness (SWT) and left ventricular mass (LVM) was examined in a large Australian FRDA cohort (n=79) with adjustments performed for GAA repeats, age, sex, body surface area and diastolic blood pressure. A significant inverse relationship was observed between GAA1 and LVIDd (p=0.010) but not with SWT or LVM after adjustment for covariates. The AGTR1 polymorphism rs5186 was more common in FRDA patients than in a control population (p=0.002). Using a recessive model of inheritance, the C allele of rs5186 was associated with a significant increase in SWT (p=0.003) and LVM (p=0.001). This functional polymorphism increases expression of AGTR1 by altering the binding site for miR-155, a regulatory microRNA. No significant associations with left ventricular structure were observed for the remaining RAAS polymorphisms. The AGTR1 polymorphism rs5186 appears to modify the FRDA cardiac phenotype independently of GAA1. This study supports the role of RAAS polymorphisms as modifiers of cardiac phenotype in FRDA patients.

Possible Mechanisms Underlying Aging-Related Changes in Early Diastolic Filling and Long Axis Motion—Left Ventricular Length and Blood Pressure

Background The transmitral E wave and the peak velocity of early diastolic mitral annular motion (e`) both decrease with age, but the mechanisms underlying these age-related changes are incompletely understood. This study investigated the possible contributions of blood pressure (BP) and left ventricular end-diastolic length (LVEDL) to age-related reductions in E and e`. Methods The study group were 82 healthy adult subjects <55 years of age who were not obese or hypertensive. Transmitral flow and mitral annular motion were recorded using pulsed-wave Doppler. LVEDL was measured from the mitral annular plane to the apical endocardium. Results Age was positively correlated with diastolic BP and septal wall thickness (SWT), inversely correlated with LVEDL (β = -0.25) after adjustment for sex and body surface area, but was not related to left ventricular end-diastolic diameter (LVEDD). Age was also inversely correlated with E (r = -0.36), septal e`(r = -0.53) and lateral e`(r = -0.53). On multivariable analysis, E was inversely correlated with diastolic BP and LVEDD, septal e`was inversely correlated with diastolic BP and positively correlated with SWT and LVEDL, after adjusting for body mass index, whilst lateral e`was inversely correlated with diastolic BP and positively correlated with LVEDL. Conclusion The above findings are consistent with higher BP being a contributor to age-related reductions in both E and e`and shortening of LVEDL with age being a contributor to the age-related reduction in e`. An implication of these findings is that slowing of myocyte relaxation is unlikely to be the sole, and may not be the main, mechanism underlying age-related decreases in E and e`.