Calvin Chin

High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis.

Aims High-sensitivity cardiac troponin I (cTnI) assays hold promise in detecting the transition from hypertrophy to heart failure in aortic stenosis. We sought to investigate the mechanism for troponin release in patients with aortic stenosis and whether plasma cTnI concentrations are associated with long-term outcome. Methods and results Plasma cTnI concentrations were measured in two patient cohorts using a high-sensitivity assay. First, in the Mechanism Cohort, 122 patients with aortic stenosis (median age 71, 67% male, aortic valve area 1.0 ± 0.4 cm2) underwent cardiovascular magnetic resonance and echocardiography to assess left ventricular (LV) myocardial mass, function, and fibrosis. The indexed LV mass and measures of replacement fibrosis (late gadolinium enhancement) were associated with cTnI concentrations independent of age, sex, coronary artery disease, aortic stenosis severity, and diastolic function. In the separate Outcome Cohort, 131 patients originally recruited into the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact of REgression (SALTIRE) study, had long-term follow-up for the occurrence of aortic valve replacement (AVR) and cardiovascular deaths. Over a median follow-up of 10.6 years (1178 patient-years), 24 patients died from a cardiovascular cause and 60 patients had an AVR. Plasma cTnI concentrations were associated with AVR or cardiovascular death HR 1.77 (95% CI, 1.22 to 2.55) independent of age, sex, systolic ejection fraction, and aortic stenosis severity. Conclusions In patients with aortic stenosis, plasma cTnI concentration is associated with advanced hypertrophy and replacement myocardial fibrosis as well as AVR or cardiovascular death.

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

Background—18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. Methods and Results—Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/background ratio) was compared with CD68 (inflammation), alkaline phosphatase, and osteocalcin (calcification) immunohistochemistry of the excised valve. In 18 patients (6 aortic sclerosis, 5 mild, and 7 moderate), aortic valve computed tomography calcium scoring was performed at baseline and after 1 year. Aortic valve 18F-NaF uptake correlated with both alkaline phosphatase (r=0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=−0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193–540) to 365 (207–934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography–defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=−0.11; P=0.66). Conclusions—18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

18F-NaF Uptake Is a Marker of Active Calcification and Disease Progression in Patients with Aortic Stenosis

Background—18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. Methods and Results—Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/background ratio) was compared with CD68 (inflammation), alkaline phosphatase, and osteocalcin (calcification) immunohistochemistry of the excised valve. In 18 patients (6 aortic sclerosis, 5 mild, and 7 moderate), aortic valve computed tomography calcium scoring was performed at baseline and after 1 year. Aortic valve 18F-NaF uptake correlated with both alkaline phosphatase (r=0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=−0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193–540) to 365 (207–934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography–defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=−0.11; P=0.66). Conclusions—18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Titin-truncating variants affect heart function in disease cohorts and the general population

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis

Abstract Aims Midwall myocardial fibrosis on cardiovascular magnetic resonance (CMR) is a marker of early ventricular decompensation and adverse outcomes in aortic stenosis (AS). We aimed to develop and validate a novel clinical score using variables associated with midwall fibrosis. Methods and results One hundred forty-seven patients (peak aortic velocity (Vmax) 3.9 [3.2,4.4] m/s) underwent CMR to determine midwall fibrosis (CMR cohort). Routine clinical variables that demonstrated significant association with midwall fibrosis were included in a multivariate logistic score. We validated the prognostic value of the score in two separate outcome cohorts of asymptomatic patients (internal: n = 127, follow-up 10.3 [5.7,11.2] years; external: n = 289, follow-up 2.6 [1.6,4.5] years). Primary outcome was a composite of AS-related events (cardiovascular death, heart failure, and new angina, dyspnoea, or syncope). The final score consisted of age, sex, Vmax, high-sensitivity troponin I concentration, and electrocardiographic strain pattern [c-statistic 0.85 (95% confidence interval 0.78–0.91), P < 0.001; Hosmer–Lemeshow χ2 = 7.33, P = 0.50]. Patients in the outcome cohorts were classified according to the sensitivity and specificity of this score (both at 98%): low risk (probability score <7%), intermediate risk (7–57%), and high risk (>57%). In the internal outcome cohort, AS-related event rates were >10-fold higher in high-risk patients compared with those at low risk (23.9 vs. 2.1 events/100 patient-years, respectively; log rank P < 0.001). Similar findings were observed in the external outcome cohort (31.6 vs. 4.6 events/100 patient-years, respectively; log rank P < 0.001). Conclusion We propose a clinical score that predicts adverse outcomes in asymptomatic AS patients and potentially identifies high-risk patients who may benefit from early valve replacement.

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

93 Ejection Fraction by Cardiovascular Magnetic Resonance Predicts Adverse Outcomes Post Aortic Valve Replacement

Introduction Predicting prognosis following aortic valve replacement (AVR) in patients with aortic stenosis (AS) remains challenging. Current guidelines recommend that surgery should be offered when ejection fraction (EF) is <50%. We sought to investigate the prognostic significance of EF calculated by cardiovascular magnetic resonance (CMR) in the long term survival of patients following AVR. Methods 80 patients (69 ± 11 years old at time of surgery; 55 male) scheduled for AVR underwent CMR assessment. 52 patients had severe AS (area <1cm2), 28 patients had moderate AS (area 1.0–1.5cm2) and other qualifying reasons for AVR. 44 patients had additional coronary artery disease.Patients were categorised into three groups according to EF prior to surgery: Group 1 (EF <50%; n = 26), Group 2 (EF of 50–70%; n = 26) and Group 3 (EF >70%; n = 28). A median 5.0 ± 1.8 years follow-up was completed using the National Strategic Tracing Scheme and hospital notes. Results Univariate analysis of all cause mortality using the Kaplan-Meier estimator demonstrated significantly higher mortality in patients with Group 1 (EF <50%) compared to those in group 3 (EF >70%; .03).There was no statistical difference between group 2 (EF of 50–70%) and the remaining 2 groups. Abstract 93 Figure 1 Kaplan-Meier survival curve of all cause mortality in Group 1 (EF <50%), Group 2 (EF 50–70%) and Group 3 (EF >70%) Conclusion Pre-operative EF is a significant predictor of mortality following AVR. Patients with EF <50% have the worst prognosis whereas those with EF >70% have the best prognosis. We aim to incease the sample size to determine whether a progressive decrease in EF per se even when above 50% should initiate consideration for AVR.

RISK STRATIFICATION IN PATIENTS WITH AORTIC STENOSIS USING NOVEL IMAGING APPROACHES

The prevalence of calcific aortic stenosis increases with age, occurring in 3% to 5% of individuals aged >75 years.1,2 The narrowing of the aortic valve is driven by a highly complex and intricately regulated process of inflammation, fibrosis, and calcification, which eventually results in leaflet immobility and the associated hemodynamic consequences.3 In response to the narrowed valve, left ventricular hypertrophy is initially adaptive to restore wall stress and cardiac performance. Ultimately, adverse events, such as symptoms, heart failure, and death, occur as the left ventricle decompensates. This transition from adaptation to decompensation is driven by progressive myocyte death and myocardial fibrosis.4–6 Therefore, it is important to consider aortic stenosis as a condition that affects both the valve and the myocardium.5,6 Indeed, contemporary guidelines recommend aortic valve replacement in patients with severe aortic stenosis and evidence of advanced ventricular decompensation, defined by either the presence of symptoms or an impaired systolic ejection fraction <50%.7,8 The current strategy relies heavily on the timely identification of symptoms. However, the poor prognosis associated with the development of angina, exertional dyspnea, and syncope first described by Ross and Braunwald4 in 1968 was based on younger patients with bicuspid or rheumatic disease (average age of 63 years at the time of death). Establishing symptoms in the more elderly population encountered in current clinical practice is more challenging because of their comorbidities and often sedentary lifestyles. Moreover, it is now widely recognized that left ventricular ejection fraction is not a sensitive marker of myocardial dysfunction,9,10 and impairment in ejection fraction is often a late manifestation that may not be reversible.11,12 Furthermore, there is an urgent need to improve our understanding of the pathogenesis of aortic stenosis, both …