Rosuvastatin slows the development of diastolic dysfunction in calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aims were to test the effect of rosuvastatin on the progression of left ventricular (LV) diastolic function in patients with aortic stenosis (AS), and to evaluate the use of beta-natriuretic-peptide (BNP) as a marker of diastolic dysfunction in this condition. METHODS: Sixty-one hypercholesterolemic, consecutive new referrals with moderate AS were administered rosuvastatin (Crestor) 20 mg/day for 18 months, while a further 60 subjects with normal cholesterol levels remained untreated. The LV diastolic function was determined using conventional Doppler echocardiography, tissue Doppler imaging (TDI); BNP plasma levels were monitored when subjects entered the study and then assessed prospectively at six-month intervals until the study end. RESULTS: After an 18-month (mean 73 +/- 24 weeks) period of treatment with rosuvastatin (Tx group), patients showed a significantly better diastolic function than untreated subjects (uTx group), as indicated by an isovolumic relaxation time (IVRT) (Tx 102.0 +/- 42.8 versus 97.2 +/- 19.1; p < 0.001; uTx 99.7 +/- 21.7 versus 95.2 +/- 21.8 ms; p = 0.032), E/A ratio (Tx 1.0 +/- 0.6 versus 0.9 +/- 0.3, p = 0.52; uTx 1.2 +/- 0.40 versus 0.9 +/- 0.30 versus, p = 0.006), and E/E' ratio (Tx 11.4 +/- 1.5 versus 11.4 +/- 1.8, p = 0.19; uTx 15.4 +/- 1.2 versus 12.3 +/- 1.5, p < 0.001). Similarly, at study end, plasma levels of BNP were significantly lower in the Tx group than in the uTx group [median (1st-3rd quartiles): 37.0 pg/ml (20.1-65.2 pg/ml) versus 57.1 pg/ml (46.9-98.2 pg/ml); p = 0.017]. CONCLUSION: The results of this prospective follow up study of asymptomatic patients showed that rosuvastatin treatment delays the progression of diastolic dysfunction in moderate AS when assessed using hemodynamic echocardiographic parameters or by the release of plasma physiological markers. Hence, the benefits of statin treatment in AS, which are known to affect the valve endothelium, also extend to changes affecting myocardial function itself.

Analysis of variability and reproducibility of echocardiography measurements in valvular aortic valve stenosis.

BACKGROUND: Doppler echocardiography is the most frequent method for detecting and evaluating the severity of valvular aortic stenosis. The aim of this study was to assess the variability and reproducibility of echocardiographic parameters including aortic valve area (AVA), peak aortic jet velocity (V(max)), velocity ratio (V(LVOT)/V(max)), peak gradient (G(max)) and mean gradient (G(mean)) in aortic stenosis (AS) patients. METHODS: Doppler echocardiograms were obtained from 150 randomly selected patients (56.7% male; mean age 73 +/- 9 years) with asymptomatic moderate aortic valve stenosis. The echocardiographic measurements were performed by two independent level III (expert) blinded observers. To assess intra-observer variability, we evaluated parameters of AS progression at two different times (mean of two weeks after the first examination). RESULTS: For intra-observer variability (observer 1), the variation and reproducibility coefficients were, respectively, 1.88% and 0.16 m/s for V(max), 2.08% and 0.14 for V(LVOT)/V(max) 2.05% and 0.18 cm2 for AVA, 3.89% and 5.18 mmHg for G(max) and 7.87% and 6.30 mmHg for G(mean). For inter-observer variability, the variation and reproducibility coefficients were, respectively, 2.00% and 0.14 m/s for V(max), 2.91% and 0.14 for V(LVOT)/V(max), 7.67% and 0.16 cm2 for AVA, 8.53% and 7.06 mmHg for G(mean) and 3.90% and 5.58 mmHg for G(max). Both intra- and inter-observer studies showed excellent intraclass correlation coefficients (ICC) for all echocardiographic parameters (ICC ranged from 0.943 to 0.990 for intra-observer variability and from 0.955 to 0.992 for interobserver variability). CONCLUSION: Doppler echocardiographic measurements of AVA, V(max), G(max) and G(mean) are highly reproducible when performed by expert observers. Of all echocardiographic parameters, V(max) and V(LVOT)/V(max) showed the best variability and reproducibility, and thus constitute reliable tools for clinical and research purposes in aortic stenosis diagnosis and follow-up.

Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis.

INTRODUCTION AND OBJECTIVES: Paraoxonases may exert anti-atherogenic action by reducing lipid peroxidation. Previous studies examined associations between polymorphisms in the paraoxonase 1 (PON1) gene and development of coronary artery disease (CAD), with inconsistent results. Given the similarities in clinical and pathophysiological risk factors of CAD and calcific aortic valve stenosis (CAVS), we postulated a link between PON1 alleles and CAVS progression. METHODS: We investigated the association between PON1 55 and 192 single nucleotide polymorphisms (SNPs), their enzyme activity, and CAVS progression assessed by aortic valve area and transvalvular peak velocity in 67 consecutive patients with moderate CAVS and 251 healthy controls. RESULTS: PON1 paraoxonase activity was higher in CAVS patients (P<0.001). The PON1 genotype Q192R SNP (P=0.03) and variant allele (R192) (P=0.01) frequencies differed between CAVS patients and controls. Significant association existed between PON1 enzyme activity, phenotypic effects of PON1 192 genotype polymorphisms, and CAVS progression, but not between PON1 55 and high-density lipoprotein (P=0.44) or low-density lipoprotein cholesterol (P=0.12), between 192 genotype and high-density lipoprotein (P=0.24) or low-density lipoprotein cholesterol (P=0.52). CONCLUSION: The PON1 genotype Q192R SNP has an important effect on CAVS disease progression. This study helps outline a genotype-phenotype relationship for PON1 in this unique population.

Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis.

OBJECTIVES: The objective of this study was to test the effect of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor on the progression of moderate to severe aortic stenosis as measured by echocardiography. BACKGROUND: Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis. METHODS: We performed an open-label, prospective study evaluating 121 consecutive patients with asymptomatic moderate to severe aortic stenosis (aortic valve area > or = 1.0 cm2; mean age 73.7 +/- 8.9 years; 57 men and 64 women), treated with and without rosuvastatin according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Echocardiographic, serum lipid, and inflammatory markers were measured at baseline and every 6 months for 18 months. RESULTS: Sixty-one patients (50.4%) with elevated LDL (159.7 +/- 33.4 mg/dl), aortic valve velocity (3.65 +/- 0.64 m/s), and aortic valve area (1.23 +/- 0.42 cm2) received rosuvastatin (20 mg/day), and 60 (49.6%) with a normal LDL (118.6 +/- 37.4 mg/dl), aortic valve velocity (3.62 +/- 0.61 m/s), and aortic valve area (1.20 +/- 0.35 cm2) received no statin. During a mean follow-up of 73 +/- 24 weeks, the change in aortic valve area in the control group was -0.10 +/- 0.09 cm2/year versus -0.05 +/- 0.12 cm2/year in the rosuvastatin group (p = 0.041). The increase in aortic valve velocity was 0.24 +/- 0.30 m/s/year in the control group and 0.04 +/- 0.38 m/s/year in the rosuvastatin group (p = 0.007). There was significant improvement in serum lipid and echocardiographic measures of aortic stenosis in the statin group. CONCLUSIONS: Prospective treatment of aortic stenosis with rosuvastatin by targeting serum LDL slowed the hemodynamic progression of aortic stenosis. This is the first prospective study that shows a positive effect of statin therapy for this disease process. (Rosuvastatin Affecting Aortic Valve Endothelium; http://www.clinicaltrials.gov/ct/show/NCT00114491?order = 1; NCT0014491).