Eva M. Staal

Low-Flow Aortic Stenosis in Asymptomatic Patients: Valvular–Arterial Impedance and Systolic Function From the SEAS Substudy

OBJECTIVES This study sought to assess the impact of valvuloarterial impedance on left ventricular (LV) myocardial systolic function in asymptomatic aortic valve stenosis (AS). BACKGROUND In atherosclerotic AS, LV global load consists of combined valvular and arterial resistance to LV ejection. Global load significantly impacts LV ejection fraction (EF) in symptomatic AS, but less is known about its effect on LV myocardial function in asymptomatic AS. METHODS Echocardiograms in 1,591 patients with asymptomatic AS (67 +/- 10 years, 51% hypertensive) at baseline in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study evaluating placebo-controlled combined simvastatin and ezetimibe treatment in AS were used to assess LV global load as valvuloarterial impedance and LV myocardial function as stress-corrected midwall shortening. The study population was divided into tertiles of global load. Stress-corrected midwall shortening was considered low if <87% in men and <90% in women. Low-flow AS was defined as stroke volume index <22 ml/m(2.04). RESULTS Energy loss index decreased (0.85 cm(2)/m(2) vs. 0.77 and 0.75 cm(2)/m(2)) and the prevalence of low stress-corrected midwall shortening increased (10% vs. 26% and 63%) with increasing LV global load (all p < 0.001). The EF was low in only 2% of patients. Patients with low-flow AS had higher LV global load and more often low midwall shortening than those with normal-flow AS (9.66 +/- 2.23 mm Hg/ml.m(2.04) and 77%, vs. 6.38 +/- 2.04 mm Hg/ml.m(2.04) and 30%, respectively, p < 0.001). In logistic regression analysis, LV global load was a main predictor of low stress-corrected midwall shortening independent of male sex, concentric LV geometry, LV hypertrophy (all p < 0.001), concomitant hypertension, and aortic regurgitation. CONCLUSIONS LV global load impacts LV myocardial function in asymptomatic AS independent of other main covariates of LV systolic function. LV myocardial systolic dysfunction is common in asymptomatic AS in particular in patients with low-flow AS and increased valvuloarterial afterload, whereas EF is generally preserved. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis [Narrowing of the Major Blood Vessel of the Heart]; NCT00092677).

High-intensity interval training may reduce in-stent restenosis following percutaneous coronary intervention with stent implantation A randomized controlled trial evaluating the relationship to endothelial function and inflammation.

BACKGROUND High-intensity interval training has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with coronary artery disease. The objective of this study was to evaluate this training model on in-stent restenosis following percutaneous coronary intervention for stable or unstable angina. METHODS AND RESULTS We prospectively randomized 40 patients after percutaneous coronary intervention with implantation of a bare metal stent (n = 30) or drug eluting stent (n = 32) to a 6-month supervised high-intensity interval exercise training program (n = 20) or to a control group (n = 20). At six months, restenosis, measured as in-segment late luminal loss of the stented coronary area, was smaller in the training group 0.10 (0.52) mm compared to the control group 0.39 (0.38) mm (P = .01). Reduction of late luminal loss in the training group was consistent with both stent types. Peak oxygen uptake increased in the training and control group by 16.8% and 7.8%, respectively (P < .01). Flow-mediated dilation improved 5.2% (7.6) in the training group and decreased -0.1% (8.1) in the control group (P = .01). Levels of high-sensitivity C-reactive protein decreased by -0.4 (1.1) mg/L in the training group and increased by 0.1 (1.2) mg/L in the control group (P = .03 for trend). CONCLUSIONS Regular high-intensity interval exercise training was associated with a significant reduction in late luminal loss in the stented coronary segment. This effect was associated with increased aerobic capacity, improved endothelium function, and attenuated inflammation.

Factors Influencing Left Ventricular Structure and Stress-Corrected Systolic Function in Men and Women With Asymptomatic Aortic Valve Stenosis (a SEAS Substudy)

To identify determinants of left ventricular (LV) structure and stress-corrected systolic function in men and women with asymptomatic aortic stenosis (AS), Doppler echocardiography was performed at baseline in 1,046 men and 674 women 28 to 86 years of age (mean 67 +/- 10) recruited in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study evaluating placebo-controlled combined simvastatin and ezetimibe treatment in AS. LV hypertrophy was less prevalent in women despite older age, higher systolic blood pressure, and smaller aortic valve area/body surface area (all p values <0.05). In logistic regression analyses, LV hypertrophy was independently associated with male gender, severity of AS, hypertension, higher systolic blood pressure, and lower stress-corrected midwall shortening (scMWS) or stress-corrected fractional shortening (scFS; all p values <0.01). In men aortic regurgitation also was a predictor of LV hypertrophy (p <0.05). Women had greater scFS and scMWS when corrected for LV size or geometry (all p values <0.001). In multivariate analyses, female gender predicted 11% greater scFS and 4% greater scMWS independent of age, body mass index, heart rate, aortic valve area, LV mass, relative wall thickness, aortic regurgitation, hypertension, and end-systolic stress (R(2) = 0.23 and 0.59, respectively, p <0.001). In conclusion, the major determinants of LV hypertrophy in patients with asymptomatic AS are male gender, severity of AS, and concomitant hypertension. Women have higher stress-corrected indexes of systolic function independent of LV geometry or size, wall stress, older age, or more concomitant hypertension.

Hypertension in Aortic Stenosis Implications for Left Ventricular Structure and Cardiovascular Events

The impact of hypertension on left ventricular structure and outcome during progression of aortic valve stenosis has not been reported from a large prospective study. Data from 1616 patients with asymptomatic aortic stenosis randomized to placebo-controlled treatment with combined simvastatin and ezetimibe in the Simvastatin Ezetimibe in Aortic Stenosis Study were used. The primary study end point included combined cardiovascular death, aortic valve events, and ischemic cardiovascular events. Hypertension was defined as history of hypertension or elevated baseline blood pressure. Left ventricular hypertrophy was defined as left ventricular mass/height2.7 ≥46.7 g/m2.7 in women and ≥49.2 g/m2.7 in men and concentric geometry as relative wall thickness ≥0.43. Baseline peak aortic jet velocity and aortic stenosis progression rate did not differ between hypertensive (n=1340) and normotensive (n=276) patients. During 4.3 years of follow-up, the prevalence of concentric left ventricular hypertrophy increased 3 times in both groups. Hypertension predicted 51% higher incidence of abnormal LV geometry at final study visit independent of other confounders (P<0.01). In time-varying Cox regression, hypertension did not predict increased rate of the primary study end point. However, hypertension was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold increased mortality (both P<0.01), independent of aortic stenosis severity, abnormal left ventricular geometry, in-treatment systolic blood pressure, and randomized study treatment. No impact on aortic valve replacement was found. In conclusion, among patients with initial asymptomatic mild-to-moderate aortic stenosis, hypertension was associated with more abnormal left ventricular structure and increased cardiovascular morbidity and mortality.The impact of hypertension on left ventricular structure and outcome during progression of aortic valve stenosis has not been reported from a large prospective study. Data from 1616 patients with asymptomatic aortic stenosis randomized to placebo-controlled treatment with combined simvastatin and ezetimibe in the Simvastatin Ezetimibe in Aortic Stenosis Study were used. The primary study end point included combined cardiovascular death, aortic valve events, and ischemic cardiovascular events. Hypertension was defined as history of hypertension or elevated baseline blood pressure. Left ventricular hypertrophy was defined as left ventricular mass/height2.7 ≥46.7 g/m2.7 in women and ≥49.2 g/m2.7 in men and concentric geometry as relative wall thickness ≥0.43. Baseline peak aortic jet velocity and aortic stenosis progression rate did not differ between hypertensive (n=1340) and normotensive (n=276) patients. During 4.3 years of follow-up, the prevalence of concentric left ventricular hypertrophy increased 3 times in both groups. Hypertension predicted 51% higher incidence of abnormal LV geometry at final study visit independent of other confounders ( P <0.01). In time-varying Cox regression, hypertension did not predict increased rate of the primary study end point. However, hypertension was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold increased mortality (both P <0.01), independent of aortic stenosis severity, abnormal left ventricular geometry, in-treatment systolic blood pressure, and randomized study treatment. No impact on aortic valve replacement was found. In conclusion, among patients with initial asymptomatic mild-to-moderate aortic stenosis, hypertension was associated with more abnormal left ventricular structure and increased cardiovascular morbidity and mortality. # Novelty and Significance {#article-title-41}

Impact of hypertension on left ventricular structure in patients with asymptomatic aortic valve stenosis (a SEAS substudy).

Objective Both hypertension and aortic valve stenosis induce left ventricular hypertrophy. However, less is known about the influence of concomitant hypertension on left ventricular structure in patients with aortic valve stenosis. Methods Baseline Doppler echocardiography was performed in 1720 patients with asymptomatic aortic valve stenosis (peak transaortic velocity ≥2.5 m/s and ≤4.0 m/s) recruited in the Simvastatin and Ezetimibe in Aortic Stenosis study at 173 centers in seven European countries. Patients were grouped as normotensive (n = 482) or hypertensive (n = 1238) according to history of hypertension or clinic blood pressure greater than 140 mmHg systolic or greater than 90 mmHg diastolic at baseline visits. Results Hypertensive patients were older, more obese, and included more women (all P < 0.05). Furthermore, the hypertensive group had higher wall thicknesses and left ventricular mass and higher prevalence of left ventricular hypertrophy (40 vs. 25%) and increased relative wall thickness (21 vs. 14%, both P < 0.01). On the basis of aortic valve area and energy loss the degree of aortic valve stenosis did not differ between the groups. In multivariate analysis, hypertension predicted higher left ventricular mass independent of other well known confounders including male sex, circumferential end-systolic stress, body mass index, aortic regurgitation, left ventricular ejection fraction and severity of aortic stenosis (multiple R2 = 0.30, P < 0.001). Conclusion In patients with asymptomatic aortic stenosis, concomitant hypertension significantly influences left ventricular geometry and is associated with higher left ventricular mass, relative wall thickness and higher prevalence of left ventricular hypertrophy.

Usefulness of Contrast Echocardiography for Predicting the Severity of Angiographic Coronary Disease in Non-ST-Elevation Myocardial Infarction

Guidelines recommend coronary angiography in patients with non-ST-elevation myocardial infarction (NSTEMI) within 24 to 72 hours, a requirement that cannot always be met. The aim of this study was to evaluate the potential use of contrast echocardiography in prioritizing these patients by identifying those with NSTEMI and angiographically severe coronary artery disease (CAD). Echocardiography was performed before coronary angiography in 110 patients with NSTEMI (67 ± 12 years old, 31% women). Segmental myocardial perfusion and wall motion was scored using a 17-segment left ventricular model. CAD was assessed by quantitative coronary angiography. In the total study population, median troponin T level was 0.27 μg/L (0.13 to 0.86) and Thrombolysis In Myocardial Infarction risk score 3.1 ± 1.5. By quantitative coronary angiography 15% had normal coronary angiographic findings, whereas 1-, 2-, and 3-vessel disease were present in 35%, 27%, and 23%, respectively. Severe CAD (left main stem stenosis, 3-vessel disease, or multivessel disease including proximal stenosis in left anterior descending artery) was found in 42%. Number of segments with hypoperfusion increased with CAD severity from 4.1 ± 2.0 in patients with normal coronary arteries to 5.9 ± 2.4, 7.8 ± 3.5, and 10.4 ± 2.8 in patients with 1-, 2-, and 3-vessel disease, respectively (p<0.01). In multiple logistic regression analysis risk of severe CAD increased by 39% for every additional hypoperfused segment by echocardiography independent of wall motion abnormalities and Thrombolysis In Myocardial Infarction risk score. In conclusion, contrast echocardiography may be used for prediction of angiographic CAD severity in patients with NSTEMI awaiting coronary angiography.

Continuous on-line measurement of absolute left ventricular volume by transcardiac conductance: angiographic validation in sheep.

ObjectiveValidation of the transcardiac conductance method for continuous, on-line measurement of absolute left ventricular volume by comparison with biplane angiography. DesignControlled, prospective animal study. SettingCatheterization laboratory of the Leiden University Medical Center. SubjectsSix anesthetized sheep. InterventionsSubjects were studied at baseline, during infusion of dobutamine, and during volume loading and beta blockade. In a pilot experiment, a coronary artery was occluded by a balloon, and the behavior of the transcardiac conductance signals during ischemia was tested. Measurements and Main ResultsCalibration factors &agr; and Vp were determined by thermodilution and hypertonic saline dilution, respectively. Calibrated transcardiac conductance volume was compared with angiographic volume in four different hemodynamic conditions, and transcardiac conductance measurements were registered during a period of ischemia. Results showed a good linear correlation between transcardiac conductance and angiographic volume (r = .77, p < .01) with an intercept of 12.5 ± 5.6 mL (interanimal variability, 17.8 mL) and a slope of 1.49 ± 0.15 (interanimal variability, 0.34). Mean &agr; and Vp were 0.12 ± 0.01 (interanimal variability, 0.07) and 104 ± 3 mL (interanimal variability, 38 mL), respectively. Vp did not vary significantly between conditions, and &agr; varied only during propranolol (p = .04). Transcardiac conductance enabled immediate visualization of acute left ventricular volume changes during coronary occlusion in a pilot experiment. ConclusionsTranscardiac conductance is a method to register an on-line, continuous, left ventricular volume signal, which correlates well with angiography. However, calibration factors need to be determined in individual subjects. The method appears promising to monitor absolute volume in the intensive care unit.

End-diastolic and end-systolic volume from the left ventricular angiogram: how accurate is visual frame selection?

Background: End-diastolic (ED), end-systolic (ES) left ventricular (LV) volumes and LV ejection fraction (LVEF) are important parameters for clinical decision making in heart disease. In clinical practice the frames from cine-angiography with the largest and smallest opacified LV areas are visually selected and the endocardial borders traced as LVED and LVES contours, respectively. We compared the accuracy of this visual method using two frames with a semi-automated computer assisted frame-by-frame analysis of the complete opacified cardiac cycles. Methods and results: In 17 patients a biplane LV cine-angiogram was obtained at 25 frames/s. Complete frame-by-frame analysis was performed using semi-automatic border detection software. Experienced independent observers visually selected and manually traced LVED and LVES in the so-called visually assessed two-frame method in a consensus meeting. LV volumes were calculated by the area–length method. Mean LVEDV, LVESV and LVEF were 133 ± 57, 56 ± 40 ml and 61 ± 16%, respectively, for the visually assessed two-frame method, and 117 ± 49, 53 ± 33 ml and 60 ± 13%, respectively, for the semi-automated computer assisted frame-by-frame method. LVEDV was significantly higher in the visually assessed two-frame method (p < 0.01). Linear regression analysis showed an excellent correlation between semi-automated computer-assisted frame-by-frame and the visually assessed two-frame LVEDV (y = 1.2x − 2.9; r2 = 0.98), LVESV (y = 1.2x − 8.2; r2 = 0.97) and good linear correlation for LVEF (y = 1.2x − 3.6; r2 = 0.82). Bland–Altman analysis showed respectively a bias of 16.4, 2.4 ml and 5.0% with overall wide limits of agreement (−6.6 and 39.4 ml; −16.6 and 21.4 ml; −9.0% and 19.1%). Conclusion: Correlation is excellent when visually assessed LVED and LVES are compared with a semi-automated computer assisted frame-by-frame analysis. However, the visually assessed two-frame method tends to overestimate the volumes obtained by semi-automated computer-assisted frame-by-frame analysis, especially for LVEDV, indicating that visual selection will yield a higher LVEF, which may influence clinical decision making.

Quantitative contrast stress echocardiography in assessment of restenosis after percutaneous coronary intervention in stable coronary artery disease

AIMS Quantitative contrast stress echocardiography (CSE) can assess regional myocardial perfusion. The aim of this study was to evaluate the performance of quantitative CSE in the detection of restenosis after percutaneous coronary intervention (PCI). METHODS AND RESULTS Thirty-three patients with stable coronary artery disease, scheduled for PCI, underwent CSE and quantitative coronary angiography (QCA) before and 9 months after PCI. Regional myocardial perfusion was analysed blinded to QCA results. QCA identified 38 significant stenoses (> or =50% diameter reduction). Before PCI, perfusion during stress was significantly reduced in regions supplied by stenotic arteries; blood flow velocity (Deltabeta) -3.9 (-9.0 to 0.5) s(-1), perfusion rate (DeltaA x beta) -175.0 (-518.0 to 58.5) s(-1), and refilling time (Deltart) 210 (-22 to 452)ms, compared with the perfusion increase seen in regions supplied by non-stenotic arteries; Deltabeta 1.6 (-0.7 to 4.4) s(-1), DeltaA x beta 151.7 (-67.0 to 300.5) s(-1), and Deltart -47 (-195 to 89) ms, all P < 0.05. At follow-up, regional stress-induced perfusion improved in 29 regions with successful PCI; Deltabeta 0.1 (-2.7 to 3.6), DeltaA x beta 30.5 (-133.3 to 232.1), and Deltart -99 (-247 to 125), all P < or = 0.01, although there was no improvement in nine regions with restenosis; Deltabeta 0.9 (-1.5 to 5.3), DeltaAxbeta 65.7 (-40.8 to 412.6), and Deltart -79 (-268 to 163), P = NS. CONCLUSION Quantitative CSE has the potential to detect angiographically significant coronary artery stenoses as well as angiographic success after PCI.

Risk factors for exertional rhabdomyolysis with renal stress

Background Exercise-induced rhabdomyolysis denotes the exertional damage of myocytes with leakage of sarcoplasmic content into the circulation. The purpose of this study was to determine important risk factors for the development of exertional rhabdomyolysis in a temperate climate and to study the renal effects of myoglobinuria. Methods A cluster of eight military recruits was admitted to hospital due to exertional rhabdomyolysis with myoglobinuria. The patients were treated according to current guidelines with isotonic saline and alkalinisation of the urine. The eight patients were compared with a randomly selected control group of 26 healthy fellow recruits. All subjects responded to a standardised questionnaire. Results There were little differences in baseline characteristics between patients and controls. In the present study, exercise intensity, duration and type were all significant determinants of exertional rhabdomyolysis in univariate models. However, in a multivariate model, high exercise intensity on day −1 was the only significant predictor of rhabdomyolysis (p=0.02). All patients had a stable serum creatinine and cystatin C. There was a significant increase in serum neutrophil gelatinase-associated lipocalin (NGAL) in the patients, suggesting renal stress. Conclusions Sustained maximal intensity exercise is a crucial risk factor for rhabdomyolysis with gross pigmenturia. Elevated serum NGAL concentrations indicate the presence of renal stress. It appears to be possible to quantify the risk of rhabdomyolysis by means of a simple questionnaire. In the future, this may be used as a tool to prevent rhabdomyolysis.