1 Heart failure

What is heart failure?

The main function of the heart is to pump blood, providing power to promote blood circulation to meet the metabolic needs of tissue cells throughout the body.

Heart failure is when the heart's systolic or diastolic function declines, resulting in a failure of cardiac output to meet the body's metabolic needs. Heart failure is the severe and terminal stage of various heart diseases. According to the patients at all stages, patients including hypertension, coronary heart disease and diabetes are at risk of heart failure.

Figure 1

Clinical status and influence of heart failure

The global incidence of chronic heart failure is 3 percent among adults and as high as 10 percent over the age of 80, according to the study. Death rates from heart failure have increased six fold over the past 40 years, and about 60 percent of patients die within five years of being diagnosed, with a five-year survival rate similar to that of malignant tumors. Heart failure also brings huge economic burden to society. In Europe and North America, the hospitalization of heart failure accounts for 1% to 4% of the hospitalization quantity, and 46% of the discharged patients are re-admitted due to the worsening of heart failure in 2 months. The average hospitalization time is 5-10 days, accounting for a large amount of medical resources, and the cost of heart failure treatment accounts for 1% to 2% of the total medical expenditure. The United States spent about $39.3 billion on heart failure in 2010, and total spending on patients with heart failure is expected to increase by 50-100% over the next 10 years. At the same time, as the end-stage patients of heart failure lose their activity and work capacity, the side effects are also very large, resulting in a huge family burden.

Figure 2

Current treatment methods and limitations

At present the treatment of heart failure mainly treated by drug therapy and placement equipment including beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, diuretics, sinoatrial node ion channel inhibitors, these made tremendous contributions to the traditional therapy for the prevention and treatment of heart failure, and improve the long-term survival of patients. However, although these laws can control the disease to a certain extent, they cannot fundamentally treat heart failure. As the disease progresses, patients with heart failure will still enter the terminal stage of the disease.

With the development of molecular biology and the research progress of human genetics, it is believed that heart failure is related to abnormal expression and regulation of some genes in cardiac cells. As a result, gene therapy is gaining attention.

What is gene therapy?

Heart failure gene therapy is through a variety of technologies such as chemical, physical or biological, will be packed with gene carrier after importing the receptor through various methods of myocardial cells or tissues, expressed through a correct or interference in heart failure pathological process of abnormal expression of target genes, so to cure or reduce symptoms of heart failure treatment. At present, the research on heart failure gene therapy mainly focuses on calcium circulation-related gene therapy, b-adrenalin signaling system related gene therapy, adenylate cyclase 6 related gene therapy, and vascular endothelial growth factor b-related gene therapy. Despite the initial difficulties in gene delivery to the heart of large animals, genetic treatment studies in preclinical large animal models have shown encouraging results. Notably, gene therapy is considered promising for heart failure. The US Food and Drug Administration has awarded MYDICAR a "breakthrough therapy" for heart failure, its first approved gene therapy. The treatment reactivates the serca2a enzyme in the body, improving the heart's ability to pump blood.

2 CaRTIN

What is RyR2? What is it made up of?

As we have introduced before, Calcium (Ca²⁺) is the important physiological ligand that activates the channels in cardiac muscle during excitation-contraction (EC) coupling. The heart dysfunction will happen when Ca²⁺ cycle is in a mess, which in the end leads to heart failure. That’s why we have to mention the Ca²⁺ release channels (a kind of ryanodine receptor) on the sarcoplasmic reticulum (SR) of striated muscles. They adjust and control Ca²⁺ between cytoplasm and SR as a biphasic channel such that low cytosolic [Ca²⁺] (mM) activates the channels and high cystolic [Ca²⁺] (mM) inactivates the channels, confirming their crucial role in EC coupling. In cardiac muscle, the Calcium release channels on the SR is named as the type 2 ryanodine receptor (RyR2). It is a tetramer comprised of four 565,000 Dalton RyR2 polypeptides and four 12,000 Dalton FK-506 binding proteins (FKBP12.6).

References

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3. Eschenhagen, T. "Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?." Journal of Clinical Investigation120.12(2010):4197-4203. Ullrich, Nina D., H. H. Valdivia, and E. Niggli. "PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity." Journal of Molecular & Cellular Cardiology 53.1(2012):33-42.
4. Marx, S. O., et al. "PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)." Cell 101.4(2000):365-376.
5. Menzel, S., et al. "Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity." Frontiers in Pharmacology9(2018):266.
6. Wikipedia. Single-domain antibody. https://en.wikipedia.org/wiki/Single-domain_antibody.
7. Wikipedia. Phage display. https://en.wikipedia.org/wiki/Phage_display.
8. Ma, X., et al. "Therapeutic delivery of cyclin-A2 via recombinant adeno-associated virus serotype 9 restarts the myocardial cell cycle: an in vitro study." Molecular Medicine Reports 11.5(2015):3652-3658.