Marie Arsenault

Usefulness of exercise-stress echocardiography for risk stratification of true asymptomatic patients with aortic valve stenosis

Aims Abnormal exercise test defined as the occurrence of exercise limiting symptoms, fall in blood pressure below baseline, or complex ventricular arrhythmias is useful to predict clinical events in asymptomatic patients with aortic stenosis (AS). The purpose of this study was to determine whether exercise-stress echocardiography (ESE) adds any incremental prognostic value to resting echocardiography in patients with AS having a normal exercise response. Methods and results One hundred and eighty-six asymptomatic patients with at least moderate AS and preserved LV ejection fraction (≥50%) were assessed by Doppler-echocardiography at rest and during a maximum ramp semi-supine bicycle exercise test. Fifty-one (27%) patients had an abnormal exercise test and were excluded from the present analysis. Among the 135 patients with normal exercise test, 67 had an event (aortic valve replacement motivated by symptoms or cardiovascular death) at a mean follow-up of 20 ± 14 months. The variables independently associated with events were: age ≥65 years [hazard ratio (HR) = 1.96; 95% confidence interval (CI): 1.15–3.47; P = 0.01], diabetes, (HR = 3.20; 95% CI: 1.33–6.87; P = 0.01), LV hypertrophy (HR = 1.96; 95% CI: 1.17–3.27; P = 0.01), resting mean gradient >35 mmHg (HR = 3.60; 95% CI: 2.11–6.37; P < 0.0001), and exercise-induced increase in mean gradient >20 mmHg (HR = 3.83; 95% CI: 2.16–6.67; P < 0.0001). Conclusion The exercise-induced increase in transvalvular gradient may be helpful to improve risk stratification in asymptomatic AS patients with normal exercise response. These results thus suggest that ESE may provide additional prognostic information over that obtained from standard exercise testing and resting echocardiography.

Experimental Aortic Valve Stenosis in Rabbits

OBJECTIVES We studied a known rabbit model of atherosclerosis to assess the effect of a hypercholesterolemic diet on aortic valve morphology and function. We also evaluated the effects of the combination of this diet with vitamin D supplements on the development of the disease and the occurrence of valve calcification. BACKGROUND Aortic valve stenosis (AVS) is the most common valvular heart disease. Recent observations have suggested a link between atherosclerosis and the development of AVS. However, until now, there has been no solid direct proof of this potential link. METHODS Rabbits were divided in three groups: 1) no treatment; 2) cholesterol-enriched diet (0.5% cholesterol); and 3) cholesterol-enriched diet plus vitamin D(2) (50,000 IU/day). Echocardiographic assessment of the aortic valve was done at baseline and after 12 weeks of treatment. The aortic valve area (AVA) and maximal and mean transvalvular gradients were recorded and compared over time. RESULTS Control animals displayed no abnormalities of the aortic valve. Despite important increases in blood total cholesterol levels, animals in group 2 did not develop any significant functional aortic valve abnormality over 12 weeks. However, eight of 10 of the animals in group 3 developed a significant decrease in AVA (p = 0.004) and significant increases in transvalvular gradients (p = 0.003). CONCLUSIONS This study supports a potential link between atherosclerosis and the development of AVS. The differences noted between hypercholesterolemic animals with or without vitamin D(2) supplementation imply a significant role of calcium in the development of AVS, meriting further attention.

Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF.

The objective of this study was to examine the value of stress-echocardiography in patients with paradoxical low-flow, low-gradient (PLFLG) aortic stenosis (AS). The projected aortic valve area (AVAProj) at a normal flow rate was calculated in 55 patients with PLFLG AS. In the subset of patients (n = 13) who underwent an aortic valve replacement within 3 months after stress echocardiography, AVA(Proj) correlated better with the valve weight compared to traditional resting and stress echocardiographic parameters of AS severity (AVA(Proj): r = -0.78 vs. other parameters: r = 0.46 to 0.56). In the whole group (N = 55), 18 (33%) patients had an AVA(Proj) >1.0 cm(2), being consistent with the presence of pseudo severe AS. The AVA(Proj) was also superior to traditional parameters of stenosis severity for predicting outcomes (hazard ratio: 1.32/0.1 cm(2) decrease in AVA(Proj)). In patients with PLFLG AS, the measurement of AVA(proj) derived from stress echocardiography is helpful to determine the actual severity of the stenosis and predict risk of adverse events.

Effectiveness of β-Blockade in Experimental Chronic Aortic Regurgitation

Background—Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. Methods and Results—Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, &bgr;-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of &bgr;1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. Conclusions—In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.

Variation of anatomic valve area during ejection in patients with valvular aortic stenosis evaluated by two-dimensional echocardiographic planimetry: comparison with traditional Doppler data ☆

OBJECTIVES Flow variations can affect valve-area calculation in aortic stenosis and lead to inaccuracies in the evaluation of the stenosis. Knowing that transvalvular flow varies normally within one beat, we designed this study to assess the response of the valve to intrabeat variation of flow during systole. Results were compared with flow-derived measurements. BACKGROUND Technological improvements now allow us to evaluate aortic valve area directly by short axis planimetry. This offers the possibility to perform serial planimetries during one ejection phase and analyze the intrabeat dynamic behavior of the stenotic-aortic valve and compare these measurements with flow-derived measurements. METHODS Forty echocardiograms displaying different degrees of aortic stenosis were analyzed by frame-by-frame planimetry of the valve area from onset of opening to complete closure. Maximal-mean area, opening and closing rates and ejection times were obtained and compared with Doppler-derived data. RESULTS Valve area varied during ejection. Stenotic valves opened and closed more slowly than normals and remained maximally open for a shorter period. Mean area by Doppler data corresponded more closely to maximal than to mean-planimetered area. Duration of flow was shorter than valve opening in severely stenotic valves. Discrepancies between Doppler-derived and two-dimensional (2D) measurements decreased in less stenotic valves. CONCLUSIONS Our observations reveal striking differences between the dynamics of normal and stenotic valves. Surprisingly, Doppler-derived mean-valve area correlated better with maximal-anatomic area than with mean-anatomic area in patients with aortic stenosis. Discrepancies between duration of flow and valve opening could explain this phenomenon.

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.

Influence of the menstrual cycle on the timing of acute coronary events in premenopausal women

During their reproductive years, women have a low incidence of coronary artery disease (1,2), which increases markedly 10 to 15 years after menopause (3). It has long been hypothesized that this increased risk is at least in part due to the absence of female hormones, in particular, 17 -estradiol (4). This hypothesis was supported by data from epidemiological studies, which suggested that hormone replacement therapy would protect postmenopausal women from coronary artery disease (5– 8). However, recent placebo-controlled trials designed to test the cardioprotective effects of a regimen of estrogens plus progestin have found no reduction in cardiovascular events or progression of angiographic lesions (9 –12). Nevertheless, acute administration of 17 -estradiol affects the vasculature by modulating the nitric oxide–Larginine pathway (13,14), and improves endothelial function (15) and prolongs the time to ST-segment depression and exercise time, in postmenopausal women with coronary artery disease (16). These data suggest that the acute effects of 17 -estradiol could subside rapidly when levels are low during menses. Therefore, we sought to determine whether premenopausal women would be at greater risk of developing an acute coronary event when blood levels of 17 -estradiol levels are low during the menstrual cycle.

Moderate Exercise Training Improves Survival and Ventricular Remodeling in an Animal Model of Left Ventricular Volume Overload

Background—Exercise training has beneficial effects in patients with heart failure, although there is still no clear evidence that it may impact on their survival. There are no data regarding the effects of exercise in subjects with chronic left ventricular (LV) volume overload. Using a rat model of severe aortic valve regurgitation (AR), we studied the effects of long-term exercise training on survival, development of heart failure, and LV myocardial remodeling. Methods and Results—One hundred sixty male adult rats were divided in 3 groups: sham sedentary (n=40), AR sedentary (n=80), and AR trained (n=40). Training consisted in treadmill running for up to 30 minutes, 5 times per week for 9 months, at a maximal speed of 20 m/minute. All sham-operated animals survived the entire course of the protocol. After 9 months, 65% of trained animals were alive compared with 46% of sedentary ones (P=0.05). Ejection fractions remained in the normal range (all above 60%) and LV masses between AR groups were similar. There was significantly less LV fibrosis in the trained group and lower LV filling pressures and improved echocardiographic diastolic parameters. Heart rate variability was also improved by exercise. Conclusion—Our data show that moderate endurance training is safe, does not increase the rate of developing heart failure, and most importantly, improves survival in this animal model of chronic LV volume overload. Exercise improved LV diastolic function, heart rate variability, and reduced myocardial fibrosis.

Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.

Dobutamine stress echocardiography in healthy adult male rats

BackgroundDobutamine stress echocardiography is used to investigate a wide variety of heart diseases in humans. Dobutamine stress echocardiography has also been used in animal models of heart disease despite the facts that the normal response of healthy rat hearts to this type of pharmacological stress testing is unknown. This study was performed to assess this normal response.Methods15 normal adult male Wistar rats were evaluated. Increasing doses of dobutamine were infused intravenously under continuous imaging of the heart by a 12 MHz ultrasound probe.ResultsDobutamine stress echocardiography reduced gradually LV diastolic and systolic dimensions. Ejection fraction increased by a mean of +24% vs. baseline. Heart rate increased progressively without reaching a plateau. Changes in LV dimensions and ejection fraction reached a plateau after a mean of 4 minutes at a constant infusion rate.ConclusionDSE can be easily performed in rats. The normal response is an increase in heart rate and ejection fraction and a decrease in LV dimensions. A plateau in echocardiographic measurements is obtained after 4 minutes of a constant infusion rate in most animals.