Cardiac Contractility Modulation Therapy in Patients with Amyloid Cardiomyopathy and Heart Failure, Case Report, Review of the Biophysics of CCM Function, and AMY-CCM Registry Presentation

Figures

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  Figure 1. Diastolic function improvement. Baseline diastolic function E/A (A′), E/E′ septal (A″), E/E′ lateral (A‴); 12-month diastolic function E/A (B′), E/E′ septal (B″), E/E′ lateral (B‴).

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  Figure 2. Schematic representation of quantum tunnelling. (A) Old Transition state theory, aiming to understand how enzymes facilitate passage of the reaction over a static potential-energy barrier to proceed from reactants to products. (B) In quantum mechanics, particles don’t have defined positions in space, but their position is instead defined by a diffuse wave function. This is known as an aspect of Heisenberg’s uncertainty principle which implies the possibility that the edges of particle waves leak through classical barriers, a process known as quantum tunnelling. (C) Effect of external EMF could enhance the probability that a particle will tunnel across the barrier.

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  Figure 3. Schematic representation of CCM induced EM field mechanism of action on enzymes. EMFs impact may also increase the probability of quantum tunnelling by inducing proper orientation of substrates and enzymes toward each other (A,B). In addition, EMF can induce refolding of denatured enzymes which can further enhance the activity (C).

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  Figure 4. Schematic representation of early and late onset effects on CCM function (see explanation in the text. The left panel refers to early onset effect which are related to enzyme modulation by CCM induced EMF (green positive circle refers to mechanism depicted in Figure 3). An increase in the phosphorylation state of troponin and myosin binding protein C leads to positive inotropy. An increase in the phosphorylation state of PLB and titin leads to positive lusitropy. PKA = phosphokinase A; PKB = phosphokinase B. The right panel refers to late onset effects which are related to DNA transcription modulation by CCM induces EMF (see Figure 5 for detailed mechanism on DNA strands). There is a substantial fetal gene reverse remodelling by increasing the down regulated RyR2, SERCA, and α-MHC. Moreover, the increase in Chaperones transcription (such as HSP70) has several positive effects such as aggregation prevention, detoxification, and disaggregation of misfolded proteins.

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  Figure 5. Schematic representation on CCM action on DNA and protein synthesis. CCM improves myocardial gene expression by EM field action on specific DNA sequences (nCTCTn, (A)). EM fields displace electrons, and this causes transient charging of small groups of DNA base pairs. At the charged sites, disaggregation forces overcome H-bonds. Disaggregation of the two chains at those sites enables transcription (B).

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  Figure 6. Cardiac Amyloid phatophysiology and CCM therapeutic effect. See explanation in the text. TTR: transtiretin. CCM: cardiac contractility modulation; LC: light chains; IG: immune globulin; ROS: reactive oxygen species; P 38 MAPK: p38 mitogen activated protein kinase.