In this observational sub-study from the ASTRONOMER trial, we sought to determine whether statin therapy improved diastolic dysfunction in patients with mild to moderate AS after a median follow-up of 3.5 years. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin arms. In patients with increasing severity of AS in groups I and II, the lateral E' decreased and the E/E' increased over time within each arm, despite no change in LV mass nor LVEF (p < 0.05). However, there was no difference in progression of diastolic dysfunction from baseline to follow-up between patients in all three predefined groups with AS who received placebo versus rosuvastatin. To the best of our knowledge, this is the first clinical investigation that specifically examined the effects of statins on the progression of diastolic dysfunction in patients with AS.
From a pathophysiologic perspective, the obstruction imposed on the LV from the stenotic AV produces systolic wall stress, which in turn leads to concentric LVH [2–4]. Although the increased LV mass may help in maintaining overall systolic function, an impairment in diastolic function arises [2–4]. The spectrum of diastolic abnormalities include increased myocardial stiffness, reduced LV compliance, and elevated left atrial and LV end-diastolic pressures [2–4]. These diastolic abnormalities eventually lead to the clinical manifestations of angina, dyspnea, and pulmonary congestion [2–4].
It has been suggested that statins may have beneficial effects on diastolic parameters, predominantly by attenuating the degree of LVH and cardiac fibrosis in murine models of hypertension [16, 17]. Indolfi et al. examined the effect of simvastatin on chronic pressure-overloaded left ventricles in Wistar rats . The administration of simvastatin significantly reduced renin angiotensin system (RAS) membrane targeting, RAS in vivo activation, and ERK2 phosphorylation, which prevented the development of LVH in this murine model of chronic pressure overload. Similarily, Luo et al. demonstrated that simvastatin reduced LVH due to inhibition of local cardiac angiotensin converting enzyme (ACE) activity .
A number of clinical studies have evaluated diastolic dysfunction in patients with varying degrees of AS severity [8–12]. We previously demonstrated that in patients with mild to moderate AS (AVA 1.2-1.7 cm2), measures of diastolic function were abnormal and related to increasing severity of AS . Specifically, the lateral E' was lower and the E/E' was higher with greater severity of AS . Diastolic abnormalities in a subset of patients with asymptomatic moderate AS were recently examined in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) baseline population . The severity of AS in this patient population was defined as an aortic valve area of 1.2 ± 0.4 cm2 and a mean transaortic peak velocity of 3.2 ± 0.5 cm/s . The LV diastolic function was impaired as evident from augment LV filling pressures (measured by septal E/E' and E/Vp) and impaired LV relaxation (measured by reduced septal E') . Lancelotti et al. evaluated patients with severe AS (AVA 0.8-0.2 cm2; mean gradient 45 mm Hg), in whom an E/E' ratio >14 identified a subset of patients at greater risk of future events . Finally, Bruch et al. demonstrated an impairment in diastolic function using TDI in symptomatic patients with advanced aortic AS and LVH . In this small, single centre study, 36 patients with moderate to severe AS were evaluated with a mean AVA of 0.8 ± 0.4 cm2 and mean transaortic pressure gradient of 57 ± 17 mm Hg . Bruch et al. demonstrated that the E/E' ratio allows for a reliable and reproducible estimation of LV filling pressures in patients with advanced AS, as compared to age-matched controls .
Despite the lack of clinical studies examining the effect of statins on preventing diastolic dysfunction in AS patients, a study by Fukuta et al. suggested that statin therapy may lower mortality in patients with diastolic heart failure due to its pleotropic effects in hypertension and CAD . In this non-randomized and non-blinded study involving 137 patients followed for a mean of 21 months, 34 patients with statin therapy were alive at study termination compared with 26 in the placebo group (p = 0.003) . Statin therapy also led to a trend in decreased cardiovascular hospitalizations (p = 0.08) . The findings of this study were clearly hypothesis-generating.
The results of our study are unique in that it is the first to directly evaluate the effects of statins on preventing the progression of diastolic dysfunction in patients with AS. With increasing severity of AS, the degree of diastolic dysfunction, as reflected by a lower E' and higher E/E' ratio, is in agreement with previous studies described above [8–12]. However, as statin therapy did not prevent the progression of AS in multiple randomized controlled studies including ASTRONOMER, SEAS and SALTIRE, [12, 19, 20] it is not unexpected that the degree of diastolic dysfunction continued to progress in our patient population. Following open surgical or percutaneous aortic valve replacement, it has been shown that diastolic parameters improve in both short and long term follow-up [10, 21, 22]. It it also plausible that our study population may have other contributing mechanisms to progressive diastolic dysfunction including underlying asymptomatic CAD that could affect the subsequent outcome.
There were some important limitations in the current study. This was an observational sub-study of the ASTRONOMER trial. The original sample size was intended to answer the primary question of whether statins affect the progression of mild to moderate AS, rather than to evaluate the effects of statins on preventing diastolic dysfunction. Given the subgroup nature of these analyses, the results of the current study need to be interpreted cautiously. Although the ASTRONOMER study included 272 patients in total, the current subanalysis study included only 168 patients in whom diastolic echocardiographic parameters were available both at baseline and at study end. Furthermore, the sample size may have been too small to detect true changes even if they exist. Similar to other studies using TDI, the methodology is angle dependent and can be affected by cardiac translation, rotation or both. Additional measurements of diastolic function including medial TDI, LA volumes, strain, strain rate and Vp were not available. Finally, the baseline patients in the ASTRONOMER trial represent a fairly homogenous, Caucasian population, and therefore, it is difficult to extrapolate these results to other ethnic groups.