Russell J. Everett

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)

Assessment of myocardial fibrosis with T1 mapping MRI

Myocardial fibrosis can arise from a range of pathological processes and its presence correlates with adverse clinical outcomes. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of cardiac structure, function, and tissue characteristics, which includes late gadolinium enhancement (LGE) techniques to identify focal irreversible replacement fibrosis with a high degree of accuracy and reproducibility. Importantly the presence of LGE is consistently associated with adverse outcomes in a range of common cardiac conditions; however, LGE techniques are qualitative and unable to detect diffuse myocardial fibrosis, which is an earlier form of fibrosis preceding replacement fibrosis that may be reversible. Novel T1 mapping techniques allow quantitative CMR assessment of diffuse myocardial fibrosis with the two most common measures being native T1 and extracellular volume (ECV) fraction. Native T1 differentiates normal from infarcted myocardium, is abnormal in hypertrophic cardiomyopathy, and may be particularly useful in the diagnosis of Anderson-Fabry disease and amyloidosis. ECV is a surrogate measure of the extracellular space and is equivalent to the myocardial volume of distribution of the gadolinium-based contrast medium. It is reproducible and correlates well with fibrosis on histology. ECV is abnormal in patients with cardiac failure and aortic stenosis, and is associated with functional impairment in these groups. T1 mapping techniques promise to allow earlier detection of disease, monitor disease progression, and inform prognosis; however, limitations remain. In particular, reference ranges are lacking for T1 mapping values as these are influenced by specific CMR techniques and magnetic field strength. In addition, there is significant overlap between T1 mapping values in healthy controls and most disease states, particularly using native T1, limiting the clinical application of these techniques at present.

Midwall Fibrosis and 5-Year Outcome in Moderate and Severe Aortic Stenosis

Aortic stenosis (AS) is characterized by progressive narrowing of the valve and the hypertrophic response of the left ventricle (LV) that ensues [(1)][1]. Although initially adaptive, the hypertrophic response ultimately decompensates and patients transition from hypertrophy to heart failure,

The Role of Imaging in Aortic Valve Disease.

Purpose of ReviewAortic valve disease is the most common form of heart valve disease in developed countries. Imaging remains central to the diagnosis and risk stratification of patients with both aortic stenosis and regurgitation and has traditionally been performed with echocardiography. Indeed, echocardiography remains the cornerstone of aortic valve imaging as it is cheap, widely available and provides critical information concerning valve hemodynamics and ventricular function.Recent FindingsWhilst diagnostic in the vast majority of patients, echocardiography has certain limitations including operator variability, potential for measurement errors and internal inconsistencies in severity grading. In particular, low-gradient severe aortic stenosis is common and challenging to diagnose. Aortic valve imaging may therefore be improved with alternative and complimentary multimodality approaches.SummaryThis review investigates established and novel techniques for imaging both the aortic valve and the myocardial remodelling response including echocardiography, computed tomography, cardiovascular magnetic resonance and positron emission tomography. Moreover, we examine how the complementary information provided by each modality may be used in both future clinical practice and the research arena.

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.

T1 Mapping in Aortic Stenosis

Aortic stenosis is the most clinically important valve disease in the Western world and is set to increase with an aging population. It is defined not only by inflammation and calcification of the valve tissue itself, but progressive hypertrophy and myocardial fibrosis of the left ventricle. Cardiac magnetic resonance (CMR) is ideally positioned to provide accurate assessment of the myocardium, allowing gold-standard quantification of the left ventricular mass. Although focal replacement fibrosis is common in patients with aortic stenosis and can be detected with the late gadolinium enhancement technique, it appears to be irreversible, making assessment of the earlier reversible stages of diffuse myocardial fibrosis desirable.

Timing of intervention in aortic stenosis: a review of current and future strategies

### Learning objectivesnnAortic stenosis (AS)xa0is the most common valve disease requiring surgical intervention in high-income countries.1 It is characterised by progressive thickening, fibrosis and calcification of the leaflets leading to restriction and valve obstruction.2 The consequent increase in left ventricular afterload leads to a hypertrophic response of the left ventricle, normalising wall tension and maintaining cardiac output. However, with progressive valvular stenosis, this hypertrophic response eventually decompensates resulting in symptom development, heart failure and death.nnWith no medications proven to attenuate or reverse stenosis progression, the only available treatment is valve replacement. This should ideally be performed when the risks of the disease process (ie, sudden cardiac death, irreversible functional impairment and heart failure) outweigh those of intervention (ie, procedural risk, long-term complications and potential need for reoperation). However, we frequently lack robust evidence to make accurate assessments of such risk. Deciding on the timing of valvular intervention is therefore difficult in many patients, and contemporary clinical guidelines are often underpinned by historical observational data rather than high-quality randomised controlled trials. This article will review our current understanding of the pathophysiology ofxa0AS, describe and examine the evidence behind current guideline recommendations and explore potential future strategies to optimise the timing of valve intervention.nnSince the original description of AS by Monckeberg in 1904, the decline in rheumatic fever and ageing population have led to a demographic transition towards fibrocalcific disease. For many years, fibrocalcific AS …

The challenge of co-existent moderate aortic stenosis and left ventricular systolic impairment

Aortic stenosis (AS) is the commonest cause of valvular heart disease in the western world with an estimated prevalence of up to 7% in patients aged 65 years or over (1). Characterised predominantly by progressive valve fibrosis and calcification, leading to restriction of the aortic valve cusps, the severity of AS has traditionally been defined by haemodynamic parameters assessed either invasively, or more commonly using echocardiography. In the setting of clinically significant AS, reactive hypertrophy of the left ventricle (LV) occurs in response to the associated LV pressure overload, maintaining wall stress and cardiac performance for many years if not decades. Ultimately, however, this process decompensates and patients transit from hypertrophy to symptomatic heart failure with poor clinical outcomes unless the valve is replaced.

LEFT VENTRICULAR HYPERTROPHY, MYOCARDIAL FIBROSIS AND CARDIAC DECOMPENSATION IN AORTIC STENOSIS

Myocardial fibrosis is a key process driving the transition from hypertrophy to heart failure in aortic stenosis and can be imaged with CMR.nn166 patients with aortic stenosis and 37 age and sex matched healthy volunteers underwent comprehensive clinical, imaging and biomarker evaluation. The burden