Audrey C. White

Left Ventricular Hypertrophy with Strain and Aortic Stenosis

Background— ECG left ventricular hypertrophy with strain is associated with an adverse prognosis in aortic stenosis. We investigated the mechanisms and outcomes associated with ECG strain. Methods and Results— One hundred and two patients (age, 70 years [range, 63–75 years]; male, 66%; aortic valve area, 0.9 cm2 [range, 0.7–1.2 cm2]) underwent ECG, echocardiography, and cardiovascular magnetic resonance. They made up the mechanism cohort. Myocardial fibrosis was determined with late gadolinium enhancement (replacement fibrosis) and T1 mapping (diffuse fibrosis). The relationship between ECG strain and cardiovascular magnetic resonance was then assessed in an external validation cohort (n=64). The outcome cohort was made up of 140 patients from the Scottish Aortic Stenosis and Lipid Lowering Trial Impact on Regression (SALTIRE) study and was followed up for 10.6 years (1254 patient-years). Compared with those without left ventricular hypertrophy (n=51) and left ventricular hypertrophy without ECG strain (n=30), patients with ECG strain (n=21) had more severe aortic stenosis, increased left ventricular mass index, more myocardial injury (high-sensitivity plasma cardiac troponin I concentration, 4.3 ng/L [interquartile range, 2.5–7.3 ng/L] versus 7.3 ng/L [interquartile range, 3.2–20.8 ng/L] versus 18.6 ng/L [interquartile range, 9.0–45.2 ng/L], respectively; P<0.001) and increased diffuse fibrosis (extracellular volume fraction, 27.4±2.2% versus 27.2±2.9% versus 30.9±1.9%, respectively; P<0.001). All patients with ECG strain had midwall late gadolinium enhancement (positive and negative predictive values of 100% and 86%, respectively). Indeed, late gadolinium enhancement was independently associated with ECG strain (odds ratio, 1.73; 95% confidence interval, 1.08–2.77; P=0.02), a finding confirmed in the validation cohort. In the outcome cohort, ECG strain was an independent predictor of aortic valve replacement or cardiovascular death (hazard ratio, 2.67; 95% confidence interval, 1.35–5.27; P<0.01). Conclusion— ECG strain is a specific marker of midwall myocardial fibrosis and predicts adverse clinical outcomes in aortic stenosis.

Optimization and comparison of myocardial T1 techniques at 3T in patients with aortic stenosis

Aims To determine the optimal T1 mapping approach to assess myocardial fibrosis at 3T. Methods and results T1 mapping was performed at 3T using the modified look-locker-inversion sequence in 20 healthy volunteers and 20 patients with aortic stenosis (AS). Pre- and post-contrast myocardial T1, the partition coefficient (λ; ΔRmyocardium/ΔRblood, where ΔR = 1/post-contrast T1 − 1/pre-contrast T1), and extracellular volume fraction [ECV; λ (1 − haematocrit)] were assessed. After establishing the optimal time point and myocardial region for analysis, we compared the reproducibility of these T1 measures and their ability to differentiate asymptomatic patients with AS from healthy volunteers. There was no segmental variation across the ventricle in any of the T1 measures evaluated. λ and ECV did not vary with time, while post-contrast T1 was relatively constant between 15 and 30 min. Thus, mid-cavity myocardium at 20 min was used for subsequent analyses. ECV displayed excellent intra-, inter-observer, and scan–rescan reproducibility [intra-class correlation coefficients (ICC) 1.00, 0.97, and 0.96, respectively], as did λ (ICC 0.99, 0.94, 0.93, respectively). Moreover, ECV and λ were both higher in patients with AS compared with controls (ECV 28.3 ± 1.7 vs. 26.0 ± 1.6%, P < 0.001; λ 0.46 ± 0.03 vs. 0.44 ± 0.03, P = 0.02), with the former offering improved differentiation. In comparison, scan–rescan reproducibilities for pre- and post-contrast myocardial T1 were only modest (ICC 0.72 and 0.56) with no differences in values observed between cases and controls (both P> 0.05). Conclusions ECV appears to be the most promising measure of diffuse myocardial fibrosis at 3T based upon its superior reproducibility and ability to differentiate disease from health.

Sustained Cardiovascular Actions of APJ Agonism During Renin–Angiotensin System Activation and in Patients With Heart Failure

Background—To assess cardiovascular actions of APJ agonism during prolonged (Pyr1)apelin-13 infusion and renin–angiotensin system activation. Methods and Results—Forty-eight volunteers and 12 patients with chronic stable heart failure attended a series of randomized placebo–controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions, and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography, and sphygmomanometry, respectively, during brief local (0.3–3.0 nmol/min) and systemic (30–300 nmol/min) or prolonged systemic (30 nmol/min) (Pyr1)apelin-13 infusions in the presence or absence of renin–angiotensin system activation with sodium depletion or angiotensin II coinfusion. During sodium depletion and angiotensin II coinfusion, (Pyr1)apelin-13–induced vasodilatation was preserved (P<0.02 for both). Systemic intravenous (Pyr1)apelin-13 infusion increased cardiac index, whereas reducing mean arterial pressure and peripheral vascular resistance index (P<0.001 for all) irrespective of sodium depletion or angiotensin II (0.5 ng/kg per minute) coinfusion (P>0.05 for all). Prolonged 6-hour (Pyr1)apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P<0.001 for all). Conclusions—APJ agonism has sustained cardiovascular effects that are preserved in the presence of renin–angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00901719, NCT00901888, NCT01049646, NCT01179061.

Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis

Objectives Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. Background Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. Methods In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. Results iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m2 vs. 16.1 ± 3.2 ml/m2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m2; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009). Conclusions CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936)

Echocardiography underestimates stroke volume and aortic valve area: implications for patients with small-area low-gradient aortic stenosis.

Background Discordance between small aortic valve area (AVA; < 1.0 cm2) and low mean pressure gradient (MPG; < 40 mm Hg) affects a third of patients with moderate or severe aortic stenosis (AS). We hypothesized that this is largely due to inaccurate echocardiographic measurements of the left ventricular outflow tract area (LVOTarea) and stroke volume alongside inconsistencies in recommended thresholds. Methods One hundred thirty-three patients with mild to severe AS and 33 control individuals underwent comprehensive echocardiography and cardiovascular magnetic resonance imaging (MRI). Stroke volume and LVOTarea were calculated using echocardiography and MRI, and the effects on AVA estimation were assessed. The relationship between AVA and MPG measurements was then modelled with nonlinear regression and consistent thresholds for these parameters calculated. Finally the effect of these modified AVA measurements and novel thresholds on the number of patients with small-area low-gradient AS was investigated. Results Compared with MRI, echocardiography underestimated LVOTarea (n = 40; −0.7 cm2; 95% confidence interval [CI], −2.6 to 1.3), stroke volumes (−6.5 mL/m2; 95% CI, −28.9 to 16.0) and consequently, AVA (−0.23 cm2; 95% CI, −1.01 to 0.59). Moreover, an AVA of 1.0 cm2 corresponded to MPG of 24 mm Hg based on echocardiographic measurements and 37 mm Hg after correction with MRI-derived stroke volumes. Based on conventional measures, 56 patients had discordant small-area low-gradient AS. Using MRI-derived stroke volumes and the revised thresholds, a 48% reduction in discordance was observed (n = 29). Conclusions Echocardiography underestimated LVOTarea, stroke volume, and therefore AVA, compared with MRI. The thresholds based on current guidelines were also inconsistent. In combination, these factors explain > 40% of patients with discordant small-area low-gradient AS.

Valvular (18)F-Fluoride and (18)F-Fluorodeoxyglucose Uptake Predict Disease Progression and Clinical Outcome in Patients With Aortic Stenosis.

18F-Fluoride is a positron emission tomography (PET) radiotracer that preferentially binds to regions of newly forming vascular microcalcifications beyond the resolution of computed tomography (CT) [(1)][1]. 18F-Fluorodeoxyglucose (18F-FDG) has been widely used to measure vascular inflammation [(2

Adverse prognosis associated with asymmetric myocardial thickening in aortic stenosis

Abstract Aims Asymmetric wall thickening has been described in patients with aortic stenosis. However, it remains poorly characterized and its prognostic implications are unclear. We hypothesized this pattern of adaptation is associated with advanced remodelling, left ventricular decompenzation, and a poor prognosis. Methods and results In a prospective observational cohort study, 166 patients with aortic stenosis (age 69, 69% males, mean aortic valve area 1.0u2009±u20090.4u2009cm2) and 37 age and sex-matched healthy volunteers underwent phenotypic characterization with comprehensive clinical, imaging, and biomarker evaluation. Asymmetric wall thickening on both echocardiography and cardiovascular magnetic resonance was defined as regional wall thickeningu2009≥u200913u2009mm andu2009>u20091.5-fold the thickness of the opposing myocardial segment. Although no control subject had asymmetric wall thickening, it was observed in 26% (nu2009=u200943) of patients with aortic stenosis using magnetic resonance and 17% (nu2009=u200929) using echocardiography. Despite similar demographics, co-morbidities, valve narrowing, myocardial hypertrophy, and fibrosis, patients with asymmetric wall thickening had increased cardiac troponin I and brain natriuretic peptide concentrations (both Pu2009<u20090.001). Over 28 [22, 33] months of follow-up, asymmetric wall thickening was an independent predictor of aortic valve replacement (AVR) or death whether detected by magnetic resonance [hazard ratio (HR)u2009=u20092.15; 95% confidence interval (CI) 1.29–3.59; Pu2009=u20090.003] or echocardiography (HRu2009=u20091.79; 95% CI 1.08–3.69; Pu2009=u20090.021). Conclusion Asymmetric wall thickening is common in aortic stenosis and is associated with increased myocardial injury, left ventricular decompenzation, and adverse events. Its presence may help identify patients likely to proceed quickly towards AVR. Clinical Trial Registration: https://clinicaltrials.gov/show/NCT01755936: NCT01755936.

B Assessment of valvular calcification and inflammation by positron emission tomography

Background The pathophysiology of aortic stenosis is incompletely understood and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods Patients with aortic sclerosis and mild, moderate and severe stenosis were prospectively compared to age and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by sodium 18-fluoride (18F-NaF) and 18-fluorodeoxyglucose (18F-FDG) uptake using positron emission tomography. Histological analysis was performed on the valves of five patients who subsequently underwent aortic valve replacement. Results 121 subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent inter-observer repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than control subjects (18F-NaF: 2.87±0.82 vs 1.55±0.17; 18F-FDG: 1.58±0.21 vs 1.30±0.13; both p<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r2=0.540, p<0.001) and colocalised to osteocalcin staining on histology. Uptake was observed both in the presence and absence of underlying calcium on CT with the latter predominating. 18F-FDG displayed a more modest increase in activity with valve severity (r2=0.218; p<0.001) and mapped to areas of macrophage accumulation. Among patients with aortic stenosis, 91% had increased 18F-NaF (>1.97) and 35% increased 18F-FDG (>1.63) uptake. A weak correlation between the activities of these tracers was observed (r2=0.174, p<0.001) and while 18F-NaF activity was higher in the aortic valve than aortic atheroma (2.68±0.84 vs 2.07±0.30; p<0.001) the reverse was true for 18F-FDG (1.56±0.21 vs 1.80±0.25; p<0.001). Conclusions Positron emission tomography is a novel, feasible and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. Calcification appears to be the predominant process that is particular to the valve and disproportionate to the degree of inflammation, indicating it to be a more attractive target for therapeutic intervention.