Aims

Cardiac amyloidosis is a common cause of heart failure with preserved ejection fraction and increasingly recognized since new diagnostic algorithms and therapeutic approaches were established during recent years. Mitochondrial dysfunction is known to play a key role in different etiologies of human heart failure but its role in cardiac amyloidosis remains unclear, although increased oxygen demand and reduced myocardial efficiency have been described in patients with cardiac amyloidosis.

Here we investigated for the first time myocardial mitochondrial function in endomyocardial biopsies from humans with different types of cardiac amyloidosis.

Methods 

Endomyocardial biopsies (EMB) of 29 patients were classified by state-of-the-art histology as transthyretin amyloidosis (ATTR, n= 9), light chain amyloidosis (AL, 5) or hypertrophic cardiomyopathy without storage disease (HCM, 7) and were compared to controls (C, 8), who were referred to EMB to exclude myocardial disease. Mitochondrial oxidative capacity was investigated by high-resolution respirometry in all biopsies. Quantitative immune cell infiltration was assessed by digital image analyses of immunohistochemistry. Additionally, we performed in-depth cardiac phenotyping by cardiovascular magnetic resonance and right heart catheterization in a smaller subgroup.  

Results

Mitochondrial respiration was impaired in patients with light chain amyloidosis and hypertrophic cardiomyopathy but not in those with transthyretin amyloidosis (figure 1).  Patients with light chain amyloidosis revealed higher counts of inflammatory cell infiltration (CD3+: 12.5 ± 2.2 (AL) vs. 3.8 ± 2.16 (ATTR) vs. 8 ± 2.53 (HCM) vs. 3.1 ± 1.44 (C) cells/mm², p= 0.03) and mitochondrial oxidative capacity inversely correlated to CD3+ cell infiltration (state 3 respiration: r= -0.59, R²= 0.35, p= 0.036) in patients with cardiac amyloidosis.   Patients with ATTR were older (64 ± 4.2 (AL) vs. 78 ± 3.4 (ATTR) vs. 53 ± 7.2 (HCM) vs. 57 ± 3.4 (C) years, p< 0.001) and had pronounced septum hypertrophy (16.4 ± 1.1 (AL) vs. 24.8 ± 1.56 (ATTR) vs. 17.2 ± 0.67 (HCM) vs. 11 ± 1.31 (C) mm, p< 0.001) compared to controls. Groups did not differ regarding sex, left ventricular ejection fraction, comorbidities or medications. 

Conclusion

Myocardial mitochondrial oxidative capacity is impaired in patients with AL but not in those with ATTR. Inflammatory cell infiltration may mediate these effects, but further studies are needed to clarify these mechanisms. 

Figure 1 Myocardial mitochondrial respiration is lower in patients with AL-Amyloidosis (AL) compared to controls but not in patients with ATTR-Amyloidosis (ATTR) regarding to the substrates (A) glutamate (C I) and (B) succinate (C II). In addition, myocardial mitochondrial respiration was lower in patients with hypertrophic cardiomyopathy without storage disease compared to controls.  Data are means ± SEM. *p< 0.05; n = 8 (control), 7 (HCM), 9 (ATTR), 5 (AL); one-way ANOVA with Dunnetts correction for multiple comparisons. AL: cardiac light chain amyloidosis; ATTR:  transthyretin cardiac amyloidosis; CETF:  electron transferring flavoprotein complex; C I: respiratory chain complex I, C II: respiratory chain complex II