Histological Validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T.

BACKGROUND: Gadolinium (Gd) Extracellular volume fraction (ECV) by Cardiovascular Magnetic Resonance (CMR) has been proposed as a non-invasive method for assessment of diffuse myocardial fibrosis. Yet only few studies used 3 T CMR to measure ECV, and the accuracy of ECV measurements at 3 T has not been established. Therefore the aims of the present study were to validate measurement of ECV by MOLLI T1 mapping by 3 T CMR against fibrosis measured by histopathology. We also evaluated the recently proposed hypothesis that native-T1 mapping without contrast injection would be sufficient to detect fibrosis. METHODS: 31 patients (age = 58 ± 17 years, 77% men) with either severe aortic stenosis (n = 12) severe aortic regurgitation (n = 9) or severe mitral regurgitation (n = 10), all free of coronary artery disease, underwent 3 T-CMR with late gadolinium enhancement (LGE) and pre- and post-contrast MOLLI T1 mapping and ECV computation, prior to valve surgery. LV biopsies were performed at the time of surgery, a median 13 [1-30] days later, and stained with picrosirius red. Pre-, and post-contrast T1 values, ECV, and amount of LGE were compared against magnitude of fibrosis by histopathology by Pearson correlation coefficients. RESULTS: The average amount of interstitial fibrosis by picrosirius red staining in biopsy samples was 6.1 ± 4.3%. ECV computed from pre-post contrast MOLLI T1 time changes was 28.9 ± 5.5%, and correlated (r = 0.78, p < 0.001) strongly with the magnitude of histological fibrosis. By opposition, neither amount of LGE (r = 0.17, p = 0.36) nor native pre-contrast myocardial T1 time (r = -0.18, p = 0.32) correlated with fibrosis by histopathology. CONCLUSIONS: ECV determined by 3 T CMR T1 MOLLI images closely correlates with histologically determined diffuse interstitial fibrosis, providing a non-invasive estimation for quantification of interstitial fibrosis in patients with valve diseases. By opposition, neither non-contrast T1 times nor the amount of LGE were indicative of the magnitude of diffuse interstitial fibrosis measured by histopathology.

Relative Contribution of Afterload and Interstitial Fibrosis to Myocardial Function in Severe Aortic Stenosis.

OBJECTIVES: The present study aimed at investigating the respective contribution of afterload and myocardial fibrosis to pre- and post-operative left ventricular (LV) function by using stress-strain relationships. BACKGROUND: Separating the effect of myocardial dysfunction and afterload on pump performance has important implications for the prognosis and management of patients with severe aortic stenosis (AS). METHODS: A total of 101 patients with isolated severe AS (57% men; mean age 71 years) and 75 healthy control subjects underwent resting 2-dimensional and speckle-tracking echocardiography to measure global circumferential strain (GCS) and global longitudinal strain (GLS), as well as end-systolic wall stress (ESWS). Normal stress-strain relationships were constructed using control subjects' data and fitted to linear regression. End-systolic stress-strain indexes (the number of SDs from the mean regression line) were used as an afterload-independent index of myocardial function and compared with myocardial fibrosis, measured on transmural myocardial biopsies harvested at the time of surgery. RESULTS: GCS and GLS were afterload-dependent in both control subjects and patients. The GLS-ESWS relationship of patients was shifted downward compared with control subjects. Patients with reduced pre-operative end-systolic stress-strain indexes exhibited larger degrees of interstitial myocardial fibrosis than patients without (3.8 ± 2.9% vs. 8.3 ± 6.3%, p < 0.001; and 4.9 ± 4.4% vs. 9.5 ± 6.4%; p < 0.001, for GLS and GCS, respectively). By multivariate analysis, pre-operative end-systolic stress-strain indexes were the only predictors of post-operative longitudinal and circumferential end-systolic stress-strain indexes (ß = 0.49 and ß = 0.60, respectively; p < 0.001). CONCLUSIONS: Myocardial strains are afterload-dependent. In patients with severe AS, pre-operative stress-strain indexes allow identification of patients with increased myocardial fibrosis and predict the extent of functional recovery after aortic valve replacement.

Natural history of paradoxical low-gradient severe aortic stenosis.

BACKGROUND: Up to 30% of patients with severe aortic stenosis (SAS; indexed aortic valve area <0.6 cm(2)/m(2)) present with low transvalvular gradient despite a normal left ventricular ejection fraction. Presently, there is intense controversy as to the prognostic implications of such findings. Accordingly, the aim of the present work was to compare the natural history of patients with paradoxical low-gradient (PLG) or high-gradient (HG) SAS. METHODS AND RESULTS: We prospectively studied 349 patients with SAS and preserved left ventricular ejection fraction. Patients were categorized into HG-SAS (n=144) and PLG-SAS (n=205) according to mean transvalvular gradient (mean gradient >40 or ≤40 mm Hg). Primary end points were all-cause mortality and echocardiographic disease progression. To evaluate natural history, patients undergoing aortic valve replacement were censored at the time of surgery (n=92). During a median follow-up of 28 months, 148 patients died. Kaplan-Meier survival curves showed better survival in PLG-SAS than in HG-SAS, both in the overall population (48% versus 31%; P<0.01) and in the asymptomatic subgroup (59% versus 35%; P<0.02). In asymptomatic patients, Cox analysis identified age, diabetes mellitus, left atrial volume, and mean gradient as independent predictors of death. Finally, at last echocardiographic follow-up, PLG-SAS demonstrated significant increases in mean gradient (from 29±6 to 38±11 mm Hg; P<0.001). CONCLUSIONS: Our study indicates that PLG-SAS is a less malignant form of AS compared with HG-SAS, because their spontaneous outcome is better. We further demonstrated that patients with PLG-SAS are en route toward the more severe HG-SAS form, because the majority of them evolve into HG-SAS over time.

Prognostic significance of LGE by CMR in aortic stenosis patients undergoing valve replacement.

BACKGROUND: Prior studies have shown that late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) can detect focal fibrosis in aortic stenosis (AS), suggesting that it might predict higher mortality risk. OBJECTIVES: This study was conducted to evaluate whether LGE-CMR can predict post-operative survival in patients with severe AS undergoing aortic valve replacement (AVR). METHODS: We prospectively evaluated survival (all-cause and cardiovascular disease related) according to LGE-CMR status in 154 consecutive AS patients (96 men; mean age: 74 ± 6 years) without a history of myocardial infarction undergoing surgical AVR and in 40 AS patients undergoing transcatheter aortic valve replacement (TAVR). RESULTS: LGE was present in 29% of patients undergoing surgical AVR and in 50% undergoing TAVR. During a median follow-up of 2.9 years, 21 patients undergoing surgical AVR and 20 undergoing TAVR died. In surgical AVR, the presence of LGE predicted higher post-operative mortality (odds ratio: 10.9; 95% confidence interval [CI]: 1.2 to 100.0; p = 0.02) and worse all-cause survival (73% vs. 88%; p = 0.02 by log-rank test) and cardiovascular disease related survival (85% vs. 95%; p = 0.03 by log-rank test) on 5-year Kaplan-Meier estimates of survival after surgical AVR. Multivariate Cox analysis identified the presence of LGE (hazard ratio: 2.8; 95% CI: 1.3 to 6.9; p = 0.025) and New York Heart Association functional class III/IV (hazard ratio: 3.2; 95% CI: 1.1 to 8.1; p < 0.01) as the sole independent predictors of all-cause mortality after surgical AVR. The presence of LGE also predicted higher all-cause mortality (p = 0.05) and cardiovascular disease related mortality (p = 0.03) in the subgroup of patients without angiographic coronary artery disease (n = 110) and higher cardiovascular disease related mortality in 25 patients undergoing transfemoral TAVR. CONCLUSIONS: The presence of LGE indicating focal fibrosis or unrecognized infarct by CMR is an independent predictor of mortality in patients with AS undergoing AVR and could provide additional information in the pre-operative evaluation of risk in these patients.

Stentless xenografts as an alternative to pulmonary homografts in the Ross operation.

OBJECTIVES: Because of the limited availability of pulmonary homografts (PH), porcine stentless xenografts (SX) have been proposed as an alternative for pulmonary valve replacement in the Ross operation. However, it is unknown whether they have similar good long-term durability. Therefore, we compared mid- to long-term outcomes between those two right ventricular outflow tract (RVOT) substitutes. METHODS: In 288 adults (>18 years) undergoing a Ross operation between 1991 and 2012, Freestyle(®) SX was used in 18 patients and a cryopreserved PH was used in 270 for RVOT reconstruction. Only patients with follow-up >2 years were included. According to the operative period, gender and age, 37 patients with PH could be matched with 17 SX patients. Clinical and echocardiographic follow-up were obtained. In a subset of patients (SX, n = 11 and PH, n = 25), a cardiac computed tomographic (CT) scan was performed to analyse graft calcification. RESULTS: The mean follow-up period was 8.2 ± 4.0 (range 2-14.6 years). During this period, 3 patients died from cancer, 2 in the SX group and 1 in the PH group (P = 0.15). No patient needed RVOT reoperation. At follow-up, RVOT peak gradient was 21 ± 5.9 mmHg in the SX and 16.3 ± 8.7 in the PH groups (P = 0.07). Peak gradient >40 mmHg was observed in only 1 patient in the PH group. Mean RVOT regurgitation was 0.1 ± 0.4 in the SX group and 0.8 ± 0.6 in the PH group (P = 0.008). CT scan analyses showed progressive calcification mainly of the graft wall, while the valve remained relatively free of calcium. Patients with the SX presented significantly higher calcium scores than those with PH (P = 0.01). CONCLUSIONS: In adult patients having the Ross operation, calcic degeneration is observed in both the PH and the SX used as pulmonary substitutes. Calcification progresses more rapidly in the SX compared with the PH. In both grafts, calcifications affect mainly the wall, while the valve remains relatively free of calcium. As a consequence, both grafts show good and similar haemodynamic outcomes at mid- to long-term follow-up. The Freestyle(®) SX can be considered as an acceptable alternative for RVOT reconstruction when PH is not available.

Aortic valve area, stroke volume, left ventricular hypertrophy, remodeling, and fibrosis in aortic stenosis assessed by cardiac magnetic resonance imaging: comparison between high and low gradient and normal and low flow aortic stenosis.

BACKGROUND: Recent works using echocardiography suggested that low gradient (LG), low flow (LF) aortic stenosis (AS) has more pronounced left ventricular (LV) concentric remodeling, smaller LV cavity size, and more interstitial fibrosis compared with high gradient (HG) normal flow (NF) AS. Therefore, we evaluated the accuracy of echocardiographic measurements and compared remodeling and fibrosis in different types of AS by cardiac magnetic resonance (CMR). METHODS AND RESULTS: A total of 128 patients (73±11 years of age; 75 men) with aortic valve area (AVA) <0.6 cm(2)/m(2) and ejection fraction >50% by echocardiography underwent CMR to measure planimetric AVA, phase-contrast indexed stroke volume, LV mass, and focal fibrosis. Using <40 mm Hg and indexed stroke volume <35 mL/m(2) by echocardiography as criteria for LG and LF, 69 (54%) patients were HG/NF, 28 (22%) HG/LF, 17 (13%) LG/NF, and 14 (11%) LG/LF AS. LV outflow tract area, indexed stroke volume, and AVA correlated well between echocardiography and CMR (r=0.7, 0.61, and 0.65, respectively; P<0.001 for all). By CMR, however, planimetric AVA was larger in LF/LG (0.54±0.08 cm(2)/m(2)) and LG/NF (0.61±0.08 cm(2)/m(2)) than in HG/LF (0.46±0.07 cm(2)/m(2); P<0.05) AS, and indexed LV mass was lower in LG/LF (75±12 g/m(2)) and LG/NF (81±18 g/m(2)) than in HG/LF (100±27 g/m(2); P<0.05) AS. All groups of AS had similar LV volumes, predominantly concentric hypertrophy remodeling, and similar amounts of focal fibrosis. CONCLUSIONS: CMR confirmed overall accuracy of echocardiographic classification of AS but demonstrated that LG/LF and LG/NF AS have larger AVA, less LV hypertrophy, and similar focal fibrosis compared with HG/LF AS. This challenges the view that LG/LF AS is a more advanced state of AS.