Tissue Doppler imaging

As in normal controls, tissue velocities in patients with CA present a similar base-to-apex gradient in all LV walls, with the highest tissue velocities at the base of each wall and progressive decreases of these velocities as the sample volume is moved toward the apex. Despite this gradient, peak systolic tissue velocities at the base and middle ventricle were significantly lower in advanced CA patients (presenting with congestive heart failure) compared to early asymptomatic patients. In contrast, peak systolic tissue velocity did not differ between the non-CA and non–congestive heart failure groups in these studies.

Strain rate and strain derived from TDI

In patients with advanced primary amyloidosis, studies of myocardial deformation quantified by TDI-derived SRI showed that systolic strain rate and strain at the basal septal segments were significantly decreased. When focusing on different directions of systolic heart function, it could be shown that although radial function was still within the normal range, longitudinal strain rate and strain were markedly reduced ( Figure 3 ). Moreover, serial investigations revealed that systolic strain rate and strain at the base and middle ventricle were significantly decreased also in asymptomatic patients with increased wall thickness. Other investigators found that systolic strain rate and strain in the basal and middle LV segments in patients with advanced CA and hypertrophy were significantly lower compared to patients with CA with normal wall thickness. Furthermore, peak longitudinal systolic strain rate and strain were decreased in all 16 LV segments of patients with CA presenting any abnormality on standard echocardiography. Interestingly, radial posterior systolic strain rate and strain were not impaired in these CA patients with LV hypertrophy. These observations support the notion that impairment of longitudinal systolic function plays a major role in CA and might be present even before congestive heart failure occurs and sometimes even in subjects with normal results on standard echocardiography. Furthermore, multivariate survival analysis identified independent predictors of clinical outcome in patients with amyloidosis, and longitudinal peak systolic basal septal strain ≤−7.5% was associated with adverse outcomes.

Radial (A) and longitudinal (B) strain rate imaging of a normal subject and a patient with CA derived from TDI. Left ventricular ejection fraction (EF) and fractional shortening (FS) in the patient with CA were 66% and 28%, respectively. Radial posterior systolic strain rate and strain are preserved, while longitudinal systolic strain rate and strain at the basal septum are significantly reduced; however, systolic strain rate and strain at the apical septum are similar to those in the normal subject. AVC = aortic valve closure.

Strain rate and strain derived from 2D STI

There are only few published studies reporting on functional abnormalities in patients with CA by STI ( Figure 4 ). Sun et al reported that global longitudinal deformation detected by STI was significantly lower in patients with CA compared to healthy controls but also to subjects with LV hypertrophy caused by hypertrophic cardiomyopathy or hypertensive heart disease. In patients with CA, some segments displayed delayed peak strain, suggesting failure of the synchronized contraction pattern that is characteristic for the pathology of these patients.

Strain and strain rate curves derived from 2D STI of the 4-chamber view from the same subjects as in Figure 3 . Three strain curves were extracted from the septal basal (yellow) , middle (blue) , and apical (green) segments. Peak systolic strain rate and strain are relatively homogenously distributed in the normal LV septum and are significantly reduced in the basal and middle septum and preserved in the apical segment in the patient with CA.

Furthermore, Kusunose et al investigated 10 patients with biopsy-proved CA using 2D STI. Peak systolic circumferential and radial strain rate and strain were calculated in the inner (endocardial half), outer (epicardial half), and transmural myocardial walls from short-axis images of the middle left ventricle. Circumferential and radial strain and strain rate of inner, outer, and transmural myocardium were all lower compared to patients with hypertension. Furthermore, segments positive for late enhancement on cardiac magnetic resonance tomography (suggesting myocardial fibrosis) showed significantly reduced radial strain and strain rate especially of the inner layer. This might be important, because these data suggest that myocardial fibrosis seems to be responsible for the markedly reduced longitudinal but also the mildly impaired radial function.

Pathomechanisms for systolic dysfunction

The underlying pathomechanisms of systolic dysfunction associated with CA remain widely unknown. Brenner et al reported that human light-chain proteins specifically alter the cellular redox state in isolated cardiomyocytes, resulting in direct impairment of cardiomyocyte contractile function and calcium handling. These direct toxic effects of the proteins induce myocardial hypertrophy, which additionally leads to impaired LV function. As the disease progresses, more amyloid deposits lead to atrophy and apoptosis of cardiomyocytes and a remodeling toward collagen formation and subsequent fibrosis. In these advanced disease stages, the impaired systolic and diastolic function is responsible for the severe symptoms with congestive heart failure.