Inflammatory and Molecular Pathways in Heart Failure-Ischemia, HFpEF and Transthyretin Cardiac Amyloidosis

Abstract

Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets.

Keywords: HFpEF; HFrEF; TTR amyloidosis; cardiac inflammation.

Figure 1

Pathogenetic therapy of TTR cardiac amyloidosis. TTR tetramers are prone to destabilization due to hereditary or wild point mutations in the TTR gene and dissociate into di- and monomers, which misfolds into an amyloidogenic form and aggregates to amyloid fibrils. TTR amyloid fibrils accumulate in the extracellular myocardium and induce cardiac dysfunction. Novel agents target singular points steps in the TTR amyloid cascade and thereby inhibit the development of TTR cardiomyopathy. siRNA (small-interfering RNA), ASO (anti-sense oligonucleotide), TUDCA/UDCA (tauroursodeoxycholic acid/ursodeoxycholic acid), SAP (SLAM-associated protein). Reprinted depictions of TTR tetramer, folded TTR di- and monomers and misfolded amyloidogenic monomer by permission from Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci USA. 2012 Jun 12;109:9629–9634: Bulawa CE, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.).