Margaret Loudon

Human non-contrast T1 values and correlation with histology in diffuse fibrosis

Background Aortic stenosis (AS) leads to diffuse fibrosis in the myocardium, which is linked to adverse outcome. Myocardial T1 values change with tissue composition. Objective To test the hypothesis that our recently developed non-contrast cardiac magnetic resonance (CMR) T1 mapping sequence could identify myocardial fibrosis without contrast agent. Design, setting and patients A prospective CMR non-contrast T1 mapping study of 109 patients with moderate and severe AS and 33 age- and gender-matched controls. Methods CMR at 1.5 T, including non-contrast T1 mapping using a shortened modified Look–Locker inversion recovery sequence, was carried out. Biopsy samples for histological assessment of collagen volume fraction (CVF%) were obtained in 19 patients undergoing aortic valve replacement. Results There was a significant correlation between T1 values and CVF% (r=0.65, p=0.002). Mean T1 values were significantly longer in all groups with severe AS (972±33 ms in severe asymptomatic, 1014±38 ms in severe symptomatic) than in normal controls (944±16 ms) (p<0.05). The strongest associations with T1 values were for aortic valve area (r=−0.40, p=0.001) and left ventricular mass index (LVMI) (r=0.36, p=0.008), and these were the only independent predictors on multivariate analysis. Conclusions Non-contrast T1 values are increased in patients with severe AS and further increase in symptomatic compared with asymptomatic patients. T1 values lengthened with greater LVMI and correlated with the degree of biopsy-quantified fibrosis. This may provide a useful clinical assessment of diffuse myocardial fibrosis in the future.

Aortic Dilation in Bicuspid Aortic Valve Disease Flow Pattern Is a Major Contributor and Differs With Valve Fusion Type

Background— Ascending aortic dilation is important in bicuspid aortic valve (BAV) disease, with increased risk of aortic dissection. We used cardiovascular MR to understand the pathophysiology better by examining the links between 3-dimensional flow abnormalities, aortic function, and aortic dilation. Methods and Results— A total of 142 subjects underwent cardiovascular MR (mean age, 40 years; 95 with BAV, 47 healthy volunteers). Patients with BAV had predominantly abnormal right-handed helical flow in the ascending aorta, larger ascending aortas (18.3±3.3 versus 15.2±2.2 mm/m2; P <0.001), and higher rotational (helical) flow (31.7±15.8 versus 2.9±3.9 mm2/s; P <0.001), systolic flow angle (23.1°±12.5° versus 7.0°±4.6°; P <0.001), and systolic wall shear stress (0.85±0.28 versus 0.59±0.17 N/m2; P <0.001) compared with healthy volunteers. BAV with right-handed flow and right-non coronary cusp fusion (n=31) showed more severe flow abnormalities (rotational flow, 38.5±16.5 versus 27.8±12.4 mm2/s; P <0.001; systolic flow angle, 29.4°±10.9° versus 19.4°±11.4°; P <0.001; in-plane wall shear stress, 0.64±0.23 versus 0.47±0.22 N/m2; P <0.001) and larger aortas (19.5±3.4 versus 17.5±3.1 mm/m2; P <0.05) than right–left cusp fusion (n=55). Patients with BAV with normal flow patterns had similar aortic dimensions and wall shear stress to healthy volunteers and younger patients with BAV showed abnormal flow patterns but no aortic dilation, both further supporting the importance of flow pattern in the pathogenesis of aortic dilation. Aortic function measures (distensibility, aortic strain, and pulse wave velocity) were similar across all groups. Conclusions— Flow abnormalities may be a major contributor to aortic dilation in BAV. Fusion type affects the severity of flow abnormalities and may allow better risk prediction and selection of patients for earlier surgical intervention.Background—Ascending aortic dilation is important in bicuspid aortic valve (BAV) disease, with increased risk of aortic dissection. We used cardiovascular MR to understand the pathophysiology better by examining the links between 3-dimensional flow abnormalities, aortic function, and aortic dilation. Methods and Results—A total of 142 subjects underwent cardiovascular MR (mean age, 40 years; 95 with BAV, 47 healthy volunteers). Patients with BAV had predominantly abnormal right-handed helical flow in the ascending aorta, larger ascending aortas (18.3±3.3 versus 15.2±2.2 mm/m2; P<0.001), and higher rotational (helical) flow (31.7±15.8 versus 2.9±3.9 mm2/s; P<0.001), systolic flow angle (23.1°±12.5° versus 7.0°±4.6°; P<0.001), and systolic wall shear stress (0.85±0.28 versus 0.59±0.17 N/m2; P<0.001) compared with healthy volunteers. BAV with right-handed flow and right-non coronary cusp fusion (n=31) showed more severe flow abnormalities (rotational flow, 38.5±16.5 versus 27.8±12.4 mm2/s; P<0.001; systolic flow angle, 29.4°±10.9° versus 19.4°±11.4°; P<0.001; in-plane wall shear stress, 0.64±0.23 versus 0.47±0.22 N/m2; P<0.001) and larger aortas (19.5±3.4 versus 17.5±3.1 mm/m2; P<0.05) than right–left cusp fusion (n=55). Patients with BAV with normal flow patterns had similar aortic dimensions and wall shear stress to healthy volunteers and younger patients with BAV showed abnormal flow patterns but no aortic dilation, both further supporting the importance of flow pattern in the pathogenesis of aortic dilation. Aortic function measures (distensibility, aortic strain, and pulse wave velocity) were similar across all groups. Conclusions—Flow abnormalities may be a major contributor to aortic dilation in BAV. Fusion type affects the severity of flow abnormalities and may allow better risk prediction and selection of patients for earlier surgical intervention.

Large-scale community echocardiographic screening reveals a major burden of undiagnosed valvular heart disease in older people: the OxVALVE Population Cohort Study.

BACKGROUND Valvular heart disease (VHD) is expected to become more common as the population ages. However, current estimates of its natural history and prevalence are based on historical studies with potential sources of bias. We conducted a cross-sectional analysis of the clinical and epidemiological characteristics of VHD identified at recruitment of a large cohort of older people. METHODS AND RESULTS We enrolled 2500 individuals aged ≥65 years from a primary care population and screened for undiagnosed VHD using transthoracic echocardiography. Newly identified (predominantly mild) VHD was detected in 51% of participants. The most common abnormalities were aortic sclerosis (34%), mitral regurgitation (22%), and aortic regurgitation (15%). Aortic stenosis was present in 1.3%. The likelihood of undiagnosed VHD was two-fold higher in the two most deprived socioeconomic quintiles than in the most affluent quintile, and three-fold higher in individuals with atrial fibrillation. Clinically significant (moderate or severe) undiagnosed VHD was identified in 6.4%. In addition, 4.9% of the cohort had pre-existing VHD (a total prevalence of 11.3%). Projecting these findings using population data, we estimate that the prevalence of clinically significant VHD will double before 2050. CONCLUSIONS Previously undetected VHD affects 1 in 2 of the elderly population and is more common in lower socioeconomic classes. These unique data demonstrate the contemporary clinical and epidemiological characteristics of VHD in a large population-based cohort of older people and confirm the scale of the emerging epidemic of VHD, with widespread implications for clinicians and healthcare resources.

A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial)

Aims Angiotensin-converting enzyme (ACE) inhibitors improve left ventricular (LV) remodelling and outcome in heart failure and hypertensive heart disease. They may be similarly beneficial in patients with aortic stenosis (AS), but historical safety concerns have limited their use, and no prospective clinical trials exist. Methods and results We conducted a prospective, randomized, double-blind, placebo-controlled trial in 100 patients with moderate or severe asymptomatic AS to examine the physiological effects of ramipril, particularly LV mass (LVM) regression. Subjects were randomized to ramipril 10 mg daily (n = 50) or placebo (n = 50) for 1 year, and underwent cardiac magnetic resonance, echocardiography, and exercise testing at 0, 6, and 12 months, with follow-up data available in 77 patients. There was a modest but progressive reduction in LVM (the primary end point) in the ramipril group vs. the placebo group (mean change −3.9 vs. +4.5 g, respectively, P = 0.0057). There were also trends towards improvements in myocardial physiology: the ramipril group showed preserved tissue Doppler systolic velocity compared with placebo (+0.0 vs. −0.5 cm/s, P = 0.04), and a slower rate of progression of the AS (valve area 0.0 cm2 in the ramipril group vs. −0.2 cm2 in the placebo arm, P = 0.067). There were no significant differences in major adverse cardiac events. Conclusion ACE inhibition leads to a modest, but progressive reduction in LVM in asymptomatic patients with moderate–severe AS compared with placebo, with trends towards improvements in myocardial physiology and slower progression of valvular stenosis. A larger clinical outcome trial to confirm these findings and explore their clinical relevance is required.

Cardiac auscultation poorly predicts the presence of valvular heart disease in asymptomatic primary care patients

Objective Cardiac auscultation is a key clinical skill, particularly for the diagnosis of valvular heart disease (VHD). However, its utility has declined due to the widespread availability of echocardiography and diminishing emphasis on the importance of clinical examination. We aim to determine the contemporary accuracy of auscultation for diagnosing VHD in primary care. Methods Cardiac auscultation was undertaken by one of two experienced general practitioners (primary care/family doctors) in a subset of 251 asymptomatic participants aged >65 years undergoing echocardiography within a large community-based screening study of subjects with no known VHD. Investigators were blinded to the echocardiographic findings. Newly detected VHD was classified as mild (mild regurgitation of any valve or aortic sclerosis) or significant (at least moderate regurgitation or mild stenosis of any valve). Results Newly identified VHD was common, with mild disease in 170/251 participants (68%) and significant disease in 36/251 (14%). The sensitivity of auscultation was low for the diagnosis of mild VHD (32%) but slightly higher for significant VHD (44%), with specificities of 67% and 69%, respectively. Likelihood ratios were not statistically significant for the diagnosis of either mild or significant VHD in the overall cohort, but showed possible value for auscultation in non-overweight subjects (body mass index <25 kg/m2). Conclusion Cardiac auscultation has limited accuracy for the detection of VHD in asymptomatic patients and is a poor diagnostic screening tool in primary care, particularly for overweight subjects. Ensuring easy access to echocardiography in patients with symptoms suggesting VHD is likely to represent a better diagnostic strategy.

A Prospective, Double-blind, Randomised Controlled Trial of the Angiotensin Converting Enzyme Inhibitor Ramipril In Asymptomatic Aortic Stenosis (RIAS trial): Trial Protocol

Background: The RIAS trial (Ramipril in Aortic Stenosis) is the first randomised, prospective, single centre, double blinded trial to examine the effects of Angiotensin Converting Enzyme (ACE) inhibition in asymptomatic Aortic Stenosis (AS). Prognosis in AS depends on how the left ventricle responds to pressure overload; severe Left Ventricular Hypertrophy (LVH) carries an adverse prognosis. ACE inhibitors reduce LVH in other conditions and may have similar benefits in patients with AS. The aims of this study were three-fold: 1) To examine the regression of LV mass and changes in other LV physiological parameters using cardiac magnetic resonance (CMR) 2) To assess the safety and tolerability of ramipril in AS 3) To examine the potential improvement in exercise tolerance Methods: 100 patients with asymptomatic moderate or severe AS will be enrolled. Patients will be randomized to placebo or ramipril (10 mg) for 12 months. At 0, 6 and 12 months, the patients will undergo a clinical assessment, phlebotomy, CMR scanning, echocardiography and a medically supervised Naughton protocol Exercise Test (ETT). Clinic checks at 2, 4, 12 and 14 weeks will be carried to titrate medication and monitor for adverse events. Results: The primary endpoint of the trial is to measure change in LV mass. Secondary endpoints include changes in LV Ejection Fraction (LVEF), diastolic function parameters, perfusion, biochemical markers of LV function and exercise tolerance. Conclusion: The RIAS trial is the first randomised, prospective, double blind trial to examine the effects of ACE inhibition in AS. If the trial is positive, our study would form the basis for a larger clinical outcome trial. Trial registration: International Standard Randomised Controlled Trial Number 24616095

Inherited Aortopathy Assessment in Relatives of Patients With a Bicuspid Aortic Valve

Bicuspid aortic valve disease (BAV) is commonly associated with aortopathy, which may be in part hemodynamically mediated [(1)][1]. BAV is known to cluster in families (≤25% family members affected) [(2)][2]. Due to this increased incidence in first-degree relatives (FDR), many clinicians will

The OxVALVE population cohort study (OxVALVE-PCS)—population screening for undiagnosed valvular heart disease in the elderly: study design and objectives

Introduction Valvular heart disease (VHD) is an increasingly important cardiac condition, driven by an ageing population and lack of progress in the development of medical therapies. There is a dearth of accurate information to guide decision-makers in the development of strategies to combat VHD, and no population-based study has been performed specifically to investigate its contemporary epidemiology. This document describes the design and methodology of the OxVALVE population cohort study (OxVALVE-PCS), which was conceived to address this need. Methods and analysis Participants aged 65 years and older attending a participating general practice in Oxfordshire, UK, are invited to attend a screening examination. Exclusion criteria include previously diagnosed VHD, inability to provide consent, terminal illness or excessive frailty. Demographics, a focused cardiovascular history and vital signs are recorded at the initial screening examination, accompanied by an echocardiogram. Any finding of significant VHD triggers a separate, more formal echocardiographic assessment (including acquisition of a three-dimensional dataset) and collection of blood samples for future genetic and biomarker analysis. Participants provide consent for longitudinal follow-up and enrolment in future cohort substudies. We also assess the acceptability of community-based echocardiographic examination and compare self-assessed quality of life between those with and without VHD. Conclusions OxVALVE-PCS will provide contemporary epidemiological data concerning the community prevalence of undiagnosed VHD, facilitate accurate deployment of scarce resources to meet the anticipated increase in demand for VHD-associated healthcare and create a series of subcohorts with carefully defined genotypes and echocardiographic phenotypes for long overdue clinical studies. Ethics and dissemination This study was approved by the local research ethics committee (Southampton, UK; REC Ref: 09/H0502/58). Results Results will be submitted for publication in peer-reviewed scientific journals.

Impaired myocardial perfusion in moderate asymptomatic aortic stenosis relates to longitudinal strain but not non-contrast T1 values

Background Myocardial perfusion and strain (in particular longitudinal strain- LS) are reduced in severe aortic stenosis (AS). It is thought that reduced perfusion occurs in the subendocardium secondary to increased LV pressure, leading to fibrosis and reduced LS. This relationship between perfusion, diffuse fibrosis and multidirectional myocardial strain has not been previously investigated in moderate (or severe) AS. We hypothesized that impaired myocardial perfusion occurs in patients with moderate AS, leading to a degree of diffuse fibrosis (reflected in increased non-contrast T1 values) and impaired longitudinal strain. Methods 32 patients with moderate AS (by echo criteria) and 12 age and sex-matched normal controls were recruited. All subjects underwent CMR scanning at 1.5T including valve assessment, stress and rest perfusion, tagging, and non-contrast T1-mapping using the ShMOLLI (Shortened Modified Look-Locker Inversion recovery) sequence, which was previously shown to have a good correlation with histological quantification of diffuse fibrosis. Myocardial perfusion reserve index (MPRI) and strain values were derived from analysis of the perfusion and tagging sequences respectively. Results Despite being well matched for age and sex, there were significant differences between patients with moderate AS and normal controls in longitudinal strain, MPRI and LV mass (p<0.0001, Table 1). There were no significant differences in circumferential strain and T1 values between the two groups. In AS patients there was a moderate correlation with MPRI and LS (r = -0.4, p<0.05), but not circumferential strain (CS). In AS patients T1 values correlated

Pre-contrast T1 mapping for detection of myocardial fibrosis in asymptomatic and symptomatic aortic stenosis

Background Aortic stenosis (AS) leads to diffuse fibrosis in the myocardium which may impair cardiac function. Existing techniques (late gadolinium enhancement [LGE]) are not good at detecting diffuse, as opposed to focal, fibrosis. Pre-contrast T1-mapping may identify changes in the myocardium without the need for exogenous contrast, and our aim was to investigate its ability to detect diffuse fibrosis in patients with AS. Methods 96 patients with moderate or severe AS were compared to 96 age-and gender-matched controls. Patients were categorized by severity of valve lesion (moderate: peak aortic velocity 3-4 m/s, severe: >4m/s) and symptoms. There were 80 asymptomatic patients under conservative management, and 16 patients with severe symptomatic AS awaiting valve replacement surgery (AVR). Biopsy samples for histological assessment of fibrosis were obtained in 11 of the latter group. All subjects underwent CMR at 1.5T which included pre-contrast T1-mapping using the Shortened Modified Look-Locker Inversion recovery (ShMOLLI) sequence. Average T1 values in the myocardium were analysed on a per-case basis.