Incremental benefit in correlation with histology of native T1 mapping, partition coefficient and extracellular volume fraction in patients with aortic stenosis

Background: We investigated the histological correlation of native T1 maps, partition coefficient and extracellular volume fraction (ECV) using an 11 heart beat (11 HB) MOLLI for identification of overall burden of fibrosis. Methods: Ten patients (8 male, age 73 ± 7 years; all in sinus rhythm, 2 with ventricular ectopy) with severe aortic stenosis (3 with coexisting coronary artery disease) scheduled for surgical aortic valve replacement underwent CMR on a 1.5T scanner (MAGNETOM Avanto, Siemens Healthcare, Erlangen). The 11HB MOLLI sequence (Siemens investigational prototype WIP 448B) was acquired before and 15 minutes post 0.1 mmol/kg gadolinium administration. Incorporating hematocrit results from the same day. This allowed native T1 maps, partition coefficient and ECV calculation. Images were obtained twice at end diastole at basal, and twice at mid left ventricular level. The average of all measurements was used to calculate ECV using the standard formula Partition Coefficient= [(1/T1myocardium post contrast-1/T1 myocardium native)]/[(1/T1 blood post contrast-1/T1 blood native)] with x(1-HCt) for ECV. Similar regions of interest were drawn in the septum at both levels for T1 values. Intraoperatively, trucut biopsies were taken from the left ventricular apical anterior/ lateral wall through the epicardium to allow histological characterization of the full myocardial wall, and fixed in warm buffered formalin. Histological analysis of formalin-fixed paraffin-embedded, transmural myocardial biopsies of the left ventricle was performed on hematoxylin/eosin and Picrosirius red-stained 3-micron-thick sections by a blinded experienced cardiac pathologist. Images were analysed using a purpose-built software (Nikon NIS elements BR) on a NIKON Eclipse light projection microscope to determine the extent of overall and reactive interstitial fibrosis, which was expressed as collagen volume fraction (%) per square millimetre. Results: Native T1 mapping, partition coefficient and ECV all correlated with histologically measured fibrosis. However, native T1 mapping showed the least accuracy (panel A, R2 = 0.42) and ECV showed the highest accuracy (panel B, R2 = 0.83). Partition coefficient was more accurate than native T1 mapping but only very marginally less so than ECV (panel C, R2 = 0.80). Conclusions: These results suggest that native T1 mapping is less accurate than partition coefficient and ECV for overall fibrosis. Therefore, post gadolinium images to enable calculation of partition coefficient and ECV should be routinely obtained to increase accuracy

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care

Left ventricular hypertrophy, fibrosis and decompensation in patients with aortic stenosis

Aortic valve stenosis is the most common valvular heart disease in the Western world. It currently affects more than 7% of the population over the age of 60, with severe stenosis affecting in excess of 3% of people over the age of 75. In parallel with an aging population, the prevalence of aortic stenosis and need for surgery are expected to double over the next 20 years increasing further the burden on healthcare resources. Left untreated aortic stenosis leads to an abnormally high pressure load on the left ventricle, a pathological process that induces myocyte hypertrophy and fibrosis. Initially, the adaptive process of increased wall thickness maintains normal wall stress, contraction and cardiac output. However, ultimately this becomes maladaptive leading to ventricular stiffness, an increase in myocyte hypertrophy and myocardial fibrosis eventually causing diastolic and systolic dysfunction and increased morbidity and mortality. At present there is no effective medical therapy capable of altering this course and aortic valve intervention, usually in the form of surgical aortic valve replacement, is recommended by international guidelines in patients with severe stenosis and evidence of LV decompensation (either on the basis of symptoms or a reduced ejection fraction). Following aortic valve intervention patients demonstrate a variable degree of regression of the ventricular hypertrophy with favorable prognosis demonstrated in the cohort of patients with the highest level of regression. In this chapter we will discuss the prevalence and mechanism of left ventricular hypertrophy, fibrosis and decompensation in patients with aortic stenosis. Through case examples we will illustrate common cases of patients with hypertrophy relating to AS and analyze the most recent guidelines from the American Heart Association/American College of Cardiology (2014) and European Society of Cardiology (2012) on managing patients with aortic stenosis

Incremental benefit in correlation with histology of native T1 mapping, partition coefficient and extracellular volume fraction in patients with aortic stenosis

Background: We investigated the histological correlation of native T1 maps, partition coefficient and extracellular volume fraction (ECV) using an 11 heart beat (11 HB) MOLLI for identification of overall burden of fibrosis. Methods: Ten patients (8 male, age 73 ± 7 years; all in sinus rhythm, 2 with ventricular ectopy) with severe aortic stenosis (3 with coexisting coronary artery disease) scheduled for surgical aortic valve replacement underwent CMR on a 1.5T scanner (MAGNETOM Avanto, Siemens Healthcare, Erlangen). The 11HB MOLLI sequence (Siemens investigational prototype WIP 448B) was acquired before and 15 minutes post 0.1 mmol/kg gadolinium administration. Incorporating hematocrit results from the same day. This allowed native T1 maps, partition coefficient and ECV calculation. Images were obtained twice at end diastole at basal, and twice at mid left ventricular level. The average of all measurements was used to calculate ECV using the standard formula Partition Coefficient= [(1/T1myocardium post contrast-1/T1 myocardium native)]/[(1/T1 blood post contrast-1/T1 blood native)] with x(1-HCt) for ECV. Similar regions of interest were drawn in the septum at both levels for T1 values. Intraoperatively, trucut biopsies were taken from the left ventricular apical anterior/ lateral wall through the epicardium to allow histological characterization of the full myocardial wall, and fixed in warm buffered formalin. Histological analysis of formalin-fixed paraffin-embedded, transmural myocardial biopsies of the left ventricle was performed on hematoxylin/eosin and Picrosirius red-stained 3-micron-thick sections by a blinded experienced cardiac pathologist. Images were analysed using a purpose-built software (Nikon NIS elements BR) on a NIKON Eclipse light projection microscope to determine the extent of overall and reactive interstitial fibrosis, which was expressed as collagen volume fraction (%) per square millimetre. Results: Native T1 mapping, partition coefficient and ECV all correlated with histologically measured fibrosis. However, native T1 mapping showed the least accuracy (panel A, R2 = 0.42) and ECV showed the highest accuracy (panel B, R2 = 0.83). Partition coefficient was more accurate than native T1 mapping but only very marginally less so than ECV (panel C, R2 = 0.80). Conclusions: These results suggest that native T1 mapping is less accurate than partition coefficient and ECV for overall fibrosis. Therefore, post gadolinium images to enable calculation of partition coefficient and ECV should be routinely obtained to increase accuracy

Association of Myocardial Fibrosis and Stroke Volume by Cardiovascular Magnetic Resonance in Patients With Severe Aortic Stenosis With Outcome After Valve Replacement: The British Society of Cardiovascular Magnetic Resonance AS700 Study

Importance: Low-flow severe aortic stenosis (AS) has higher mortality than severe AS with normal flow. The conventional definition of low-flow AS is an indexed stroke volume (SVi) by echocardiography less than 35 mL/m2. Cardiovascular magnetic resonance (CMR) is the reference standard for quantifying left ventricular volumes and function from which SVi by CMR can be derived. Objective: To determine the association of left ventricular SVi by CMR with myocardial remodeling and survival among patients with severe AS after valve replacement. Design, Setting, and Participants: This multicenter longitudinal cohort study was conducted between January 2003 and May 2015 across 6 UK cardiothoracic centers. Patients with severe AS listed for either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were included. Patients underwent preprocedural echocardiography and CMR. Patients were stratified by echocardiography-derived aortic valve mean and/or peak gradient and SVi by CMR into 4 AS endotypes: low-flow, low-gradient AS; low-flow, high-gradient AS; normal-flow, low-gradient AS; and normal-flow, high-gradient AS. Patients were observed for a median of 3.6 years. Data were analyzed from September to November 2021. Exposures SAVR or TAVR. Main Outcomes and Measures: All-cause and cardiovascular (CV) mortality after aortic valve intervention. Results: Of 674 included patients, 425 (63.1%) were male, and the median (IQR) age was 75 (66-80) years. The median (IQR) aortic valve area index was 0.4 (0.3-0.4) cm2/m2. Patients with low-flow AS endotypes (low gradient and high gradient) had lower left ventricular ejection fraction, mass, and wall thickness and increased all-cause and CV mortality than patients with normal-flow AS (all-cause mortality: hazard ratio [HR], 2.08; 95% CI, 1.37-3.14; P < .001; CV mortality: HR, 3.06; 95% CI, 1.79-5.25; P < .001). CV mortality was independently associated with lower SVi (HR, 1.64; 95% CI, 1.08-2.50; P = .04), age (HR, 2.54; 95% CI, 1.29-5.01; P = .001), and higher quantity of late gadolinium enhancement (HR, 2.93; 95% CI, 1.68-5.09; P < .001). CV mortality hazard increased more rapidly in those with an SVI less than 45 mL/m2. SVi by CMR was independently associated with age, atrial fibrillation, focal scar (by late gadolinium enhancement), and parameters of cardiac remodeling (left ventricular mass and left atrial volume). Conclusions and Relevance: In this cohort study, SVi by CMR was associated with CV mortality after aortic valve replacement, independent of age, focal scar, and ejection fraction. The unique capability of CMR to quantify myocardial scar, combined with other prognostically important imaging biomarkers, such as SVi by CMR, may enable comprehensive stratification of postoperative risk in patients with severe symptomatic AS

Association of myocardial fibrosis and stroke volume by cardiovascular magnetic resonance in patients with severe aortic stenosis with outcome after valve replacement:The British Society of Cardiovascular Magnetic Resonance AS700 Study

Importance: Low-flow severe aortic stenosis (AS) has higher mortality than severe AS with normal flow. The conventional definition of low-flow AS is an indexed stroke volume (SVi) by echocardiography less than 35 mL/m2. Cardiovascular magnetic resonance (CMR) is the reference standard for quantifying left ventricular volumes and function from which SVi by CMR can be derived. Objective To determine the association of left ventricular SVi by CMR with myocardial remodeling and survival among patients with severe AS after valve replacement. Design, Setting, and Participants: This multicenter longitudinal cohort study was conducted between January 2003 and May 2015 across 6 UK cardiothoracic centers. Patients with severe AS listed for either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were included. Patients underwent preprocedural echocardiography and CMR. Patients were stratified by echocardiography-derived aortic valve mean and/or peak gradient and SVi by CMR into 4 AS endotypes: low-flow, low-gradient AS; low-flow, high-gradient AS; normal-flow, low-gradient AS; and normal-flow, high-gradient AS. Patients were observed for a median of 3.6 years. Data were analyzed from September to November 2021. Exposures: SAVR or TAVR. Main Outcomes and Measures: All-cause and cardiovascular (CV) mortality after aortic valve intervention. Results: Of 674 included patients, 425 (63.1%) were male, and the median (IQR) age was 75 (66-80) years. The median (IQR) aortic valve area index was 0.4 (0.3-0.4) cm2/m2. Patients with low-flow AS endotypes (low gradient and high gradient) had lower left ventricular ejection fraction, mass, and wall thickness and increased all-cause and CV mortality than patients with normal-flow AS (all-cause mortality: hazard ratio [HR], 2.08; 95% CI, 1.37-3.14; P < .001; CV mortality: HR, 3.06; 95% CI, 1.79-5.25; P < .001). CV mortality was independently associated with lower SVi (HR, 1.64; 95% CI, 1.08-2.50; P = .04), age (HR, 2.54; 95% CI, 1.29-5.01; P = .001), and higher quantity of late gadolinium enhancement (HR, 2.93; 95% CI, 1.68-5.09; P < .001). CV mortality hazard increased more rapidly in those with an SVI less than 45 mL/m2. SVi by CMR was independently associated with age, atrial fibrillation, focal scar (by late gadolinium enhancement), and parameters of cardiac remodeling (left ventricular mass and left atrial volume). Conclusions and Relevance: In this cohort study, SVi by CMR was associated with CV mortality after aortic valve replacement, independent of age, focal scar, and ejection fraction. The unique capability of CMR to quantify myocardial scar, combined with other prognostically important imaging biomarkers, such as SVi by CMR, may enable comprehensive stratification of postoperative risk in patients with severe symptomatic AS