Saul G. Myerson

Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis.

OBJECTIVES This study sought to explore the potential role of noncontrast myocardial T1 mapping for detection of cardiac involvement in patients with primary amyloid light-chain (AL) amyloidosis. BACKGROUND Cardiac involvement carries a poor prognosis in systemic AL amyloidosis. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is useful for the detection of cardiac amyloid, but characteristic LGE patterns do not always occur or they appear late in the disease. Noncontrast characterization of amyloidotic myocardium with T1 mapping may improve disease detection. Furthermore, quantitative assessment of myocardial amyloid load would be of great value. METHODS Fifty-three AL amyloidosis patients (14 with no cardiac involvement, 11 with possible involvement, and 28 with definite cardiac involvement based on standard biomarker and echocardiographic criteria) underwent CMR (1.5-T) including noncontrast T1 mapping (shortened modified look-locker inversion recovery [ShMOLLI] sequence) and LGE imaging. These were compared with 36 healthy volunteers and 17 patients with aortic stenosis and a comparable degree of left ventricular hypertrophy as the cardiac amyloid patients. RESULTS Myocardial T1 was significantly elevated in cardiac AL amyloidosis patients (1,140 ± 61 ms) compared to normal subjects (958 ± 20 ms, p < 0.001) and patients with aortic stenosis (979 ± 51 ms, p < 0.001). Myocardial T1 was increased in AL amyloid even when cardiac involvement was uncertain (1,048 ± 48 ms) or thought absent (1,009 ± 31 ms). A noncontrast myocardial T1 cutoff of 1,020 ms yielded 92% accuracy for identifying amyloid patients with possible or definite cardiac involvement. In the AL amyloidosis cohort, there were significant correlations between myocardial T1 time and indices of systolic and diastolic dysfunction. CONCLUSIONS Noncontrast T1 mapping has high diagnostic accuracy for detecting cardiac AL amyloidosis, correlates well with markers of systolic and diastolic dysfunction, and is potentially more sensitive for detecting early disease than LGE imaging. Elevated myocardial T1 may represent a direct marker of cardiac amyloid load. Further studies are needed to assess the prognostic significance of T1 elevation.

The role of cardiovascular magnetic resonance imaging in heart failure.

Noninvasive imaging plays a central role in the diagnosis of heart failure, assessment of prognosis, and monitoring of therapy. Cardiovascular magnetic resonance (CMR) offers a comprehensive assessment of heart failure patients and is now the gold standard imaging technique to assess myocardial anatomy, regional and global function, and viability. Furthermore, it allows assessment of perfusion and acute tissue injury (edema and necrosis), whereas in nonischemic heart failure, fibrosis, infiltration, and iron overload can be detected. The information derived from CMR often reveals the underlying etiology of heart failure, and its high measurement accuracy makes it an ideal technique for monitoring disease progression and the effects of treatment. Evidence on the prognostic value of CMR-derived parameters in heart failure is rapidly emerging. This review summarizes the advantages of CMR for patients with heart failure and its important role in key areas.

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.

Left Ventricular Mass: Reliability of M-Mode and 2-Dimensional Echocardiographic Formulas

Abstract—The study of left ventricular (LV) hypertrophy is hindered by problems with LV mass measurement by echocardiography. Both the M-mode and 2D area-length formulas for calculating LV mass assume a fixed geometric shape, which may be a source of error. We examined this hypothesis by using cardiovascular magnetic resonance images to eliminate the confounding effects of acoustic access and image quality. LV mass was measured directly in 212 healthy subjects by means of a standard 3D cardiovascular magnetic resonance technique. LV mass was also calculated by using the cube-function and area-length formulas with measurements from the magnetic resonance images. A comparison of serial measurements was made by examining the changes in LV mass by all 3 techniques in those completing an exercise program (n=140). The cube-function technique showed a consistent underestimation of LV mass of 14.3 g, and there were wide 95% limits of agreement (±57.6 g and ±46.3 g for cube-function and area-length techniques, respectively) when compared with 3D measurement. There were similarly wide limits of agreement for the change in mass (±55.2 g and ±44.8 g for cube-function and area-length, respectively). The assumption of geometric shape in the cube-function and area-length formulas resulted in significant variation in LV mass estimates from direct measurement by using a 3D technique. The technique cannot be recommended either at a single time point or for serial studies in small populations; 3D imaging techniques, such as cardiovascular magnetic resonance, are preferable.

Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism A Randomized Controlled Trial With Losartan

BackgroundLocal cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT1) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype–associated exertional LV growth and to clarify the role of the AT1 receptor in this association. Methods and ResultsOne hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT1 receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P <0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P =0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P =0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (−0.022 versus 0.131 g/kg, respectively;P =0.0009). ConclusionsACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT1 receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.

Bradykinin B2BKR receptor polymorphism and left-ventricular growth response

Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.

Aortic Regurgitation Quantification Using Cardiovascular Magnetic Resonance Association With Clinical Outcome

Background— Current indications for surgery in patients with significant aortic regurgitation (AR) focus on symptoms and left ventricular dilation/dysfunction. However, prognosis is already reduced by this stage, and earlier identification of patients for surgery could be beneficial. Quantifying the regurgitation may help, but there are limited data on its link with outcome. Cardiovascular magnetic resonance (CMR) can accurately quantify AR, and we examined whether this was associated with the future need for surgery. Methods and Results— One hundred thirteen patients with echocardiographic moderate or severe AR were monitored for up to 9 years (mean 2.6±2.1 years) following a CMR scan, and the progression to symptoms or other indications for surgery was monitored. AR quantification identified outcome with high accuracy: 85% of the 39 subjects with regurgitant fraction >33% progressed to surgery (mostly within 3 years) in comparison with 8% of 74 subjects with regurgitant fraction ⩽33% (P<0.0001); the area under the curve on receiver operating characteristic analysis was 0.93 (P<0.0001). This ability remained strong on time-dependent Kaplan–Meier survival curves. CMR-derived left ventricular end-diastolic volume >246 mL had good, although lower, discriminatory ability (area under the curve 0.88), but the combination of this measure with regurgitant fraction provided the best discriminatory power. Conclusions— High degrees of CMR-quantified AR were associated with the development of symptoms or other indications for surgery. Quantifying AR showed slightly better discriminatory ability than “gold standard” CMR ventricular volume assessment. This could provide a new paradigm for the timing of surgical intervention but requires confirmation in a clinical trial.

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.

Phase contrast ultrashort TE: A more reliable technique for measurement of high‐velocity turbulent stenotic jets

Accurate measurement of peak velocity is critical to the assessment of patients with stenotic valvular disease. Conventional phase contrast (PC) methods for imaging high‐velocity jets in aortic stenosis are susceptible to intravoxel dephasing signal loss, which can result in unreliable measurements. The most effective method for reducing intravoxel dephasing is to shorten the echo time (TE); however, the amount that TE can be shortened in conventional sequences is limited. A new sequence incorporating velocity‐dependent slice excitation and ultrashort TE (UTE) centric radial readout trajectories is proposed that reduces TE from 2.85 to 0.65 ms. In a high‐velocity stenotic jet phantom, a conventional sequence had >5% flow error at a flow rate of only 400 mL/s (velocity >358 cm/s), whereas the PC‐UTE showed excellent agreement (<5% error) at much higher flow rates (1080 mL/s, 965 cm/s). In vivo feasibility studies demonstrated that by measuring velocity over a shorter time the PC‐UTE approach is more robust to intravoxel dephasing signal loss. It also has less inherent higher‐order motion encoding. This sequence therefore demonstrates potential as a more robust method for measuring peak velocity and flow in high‐velocity turbulent stenotic jets. Magn Reson Med, 2009.