Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF).

BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown.

METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained.

RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide.

CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Psychotic symptoms in Alzheimer's disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene

It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimer's disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimer's disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD.