Jacek Kwiecinski

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)

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 1.0 ± 0.4 cm2) 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 thickening ≥ 13 mm and > 1.5-fold the thickness of the opposing myocardial segment. Although no control subject had asymmetric wall thickening, it was observed in 26% (n = 43) of patients with aortic stenosis using magnetic resonance and 17% (n = 29) 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 P < 0.001). 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) = 2.15; 95% confidence interval (CI) 1.29–3.59; P = 0.003] or echocardiography (HR = 1.79; 95% CI 1.08–3.69; P = 0.021). 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.

Cardiac myosin-binding protein C is a novel marker of myocardial injury and fibrosis in aortic stenosis

Objective Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis. Methods cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11.3 years. Results In the mechanism cohort, cMyC concentration correlated with left ventricular mass (adjusted β=11.0 g/m2 per log unit increase in cMyC, P<0.001), fibrosis volume (adjusted β=8.0 g, P<0.001) and extracellular volume (adjusted β=1.3%, P=0.01) in patients with aortic stenosis but not in controls. In those with late gadolinium enhancement (LGE) indicative of myocardial fibrosis, cMyC concentrations were higher (32 (21–56) ng/L vs 17 (12–24) ng/L without LGE, P<0.001). cMyC was unrelated to coronary calcium scores. Unadjusted Cox proportional hazards analysis in the outcome cohort showed greater all-cause mortality (HR 1.49 per unit increase in log cMyC, 95% CI 1.11 to 2.01, P=0.009). Conclusions Serum cMyC concentration is associated with myocardial hypertrophy, fibrosis and an increased risk of mortality in aortic stenosis. The quantification of serum sarcomeric protein concentrations provides objective measures of disease severity and their clinical utility to monitor the progression of aortic stenosis merits further study. Clinical trial registration NCT1755936; Post-results.

Three-hour delayed imaging improves assessment of coronary 18F-sodium fluoride PET

Coronary 18F-sodium fluoride (18F-NaF) PET identifies ruptured plaques in patients with recent myocardial infarction and localizes to atherosclerotic lesions with active calcification. Most studies to date have performed the PET acquisition 1 h after injection. Although qualitative and semiquantitative analysis is feasible with 1-h images, residual blood-pool activity often makes it difficult to discriminate plaques with 18F-NaF uptake from noise. We aimed to assess whether delayed PET performed 3 h after injection improves image quality and uptake measurements. Methods: Twenty patients (67 ± 7 y old, 55% male) with stable coronary artery disease underwent coronary CT angiography (CTA) and PET/CT both 1 h and 3 h after the injection of 266.2 ± 13.3 MBq of 18F-NaF. We compared the visual pattern of coronary uptake, maximal background (blood pool) activity, noise, SUVmax, corrected SUVmax (cSUVmax), and target-to-background (TBR) ratio in lesions defined by CTA on 1-h versus 3-h 18F-NaF PET. Results: On 1-h PET, 26 CTA lesions with 18F-NaF PET uptake were identified in 12 (60%) patients. On 3-h PET, we detected 18F-NaF PET uptake in 7 lesions that were not identified on 1-h PET. The median cSUVmax and TBRs of these lesions were 0.48 (interquartile range [IQR], 0.44–0.51) and 1.45 (IQR, 1.39–1.52), respectively, compared with −0.01 (IQR, −0.03–0.001) and 0.95 (IQR, 0.90–0.98), respectively, on 1-h PET (both P < 0.001). Across the entire cohort, 3-h PET SUVmax was similar to 1-h PET measurements (1.63 [IQR, 1.37–1.98] vs. 1.55 [IQR, 1.43–1.89], P = 0.30), and the background activity was lower (0.71 [IQR, 0.65–0.81] vs. 1.24 [IQR, 1.05–1.31], P < 0.001). On 3-h PET, TBR, cSUVmax, and noise were significantly higher (respectively: 2.30 [IQR, 1.70–2.68] vs. 1.28 [IQR, 0.98–1.56], P < 0.001; 0.38 [IQR, 0.27–0.70] vs. 0.90 [IQR, 0.64–1.17], P < 0.001; and 0.10 [IQR, 0.09–0.12] vs. 0.07 [IQR, 0.06–0.09], P = 0.02). Median cSUVmax and TBR increased by 92% (range, 33%–225%) and 80% (range, 20%–177%), respectively. Conclusion: Blood-pool activity decreases on delayed imaging, facilitating the assessment of 18F-NaF uptake in coronary plaques. Median TBR increases by 80%, leading to the detection of more plaques with significant uptake than are detected using the standard 1-h protocol. A greater than 1-h delay may improve the detection of 18F-NaF uptake in coronary artery plaques.

Selection of abstracts from the scientific sessions of the Society of Nuclear Medicine and Molecular Imaging, Philadelphia PA June 23–26, 2018

This mini-review highlights cardiovascular studies that were presented during the 2018 Society of Nuclear Medicine and Molecular Imaging (SNMMI) annual meeting in Philadelphia. The aim of this review is to inform readers about several noteworthy studies reported at the meeting. Although cardiovascular application of PET and SPECT are not the primary focus of the SNMMI, several scientific teams working in this field presented their latest scientific findings at this meeting. The review therefore aims to inform the readers who did not attend the SNMMI annual meeting about some interesting new concepts presented this year at the conference.

CARDIAC MYOSIN BINDING PROTEIN C IS A NOVEL CIRCULATING MARKER OF MYOCARDIAL INJURY AND FIBROSIS IN PATIENTS WITH AORTIC STENOSIS

Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. Cardiac myosin binding protein C (cMyC) is a novel and highly specific marker of myocardial injury. We measured plasma cMyC in individuals with aortic stenosis and examined its