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Cardiovascular research

Developing cardiovascular treatments using drugs, cell therapy & AI

Within the field of cardiovascular therapy, there are several avenues of treatment that can be explored. The traditional approaches have focused on diagnostic tools to establish whether certain conditions within the cardiovascular system are not functioning and thus propose a risk to the function of the heart, and developing drugs that can modify, and thus normalize, the behavior of the heart1.

Additionally, cardiologists have applied interventional methods like stent placement or surgical procedures to replace valves and coronary artery by-pass operations (CABGs) to restore normal heart function.

Some of the newer treatments are antibody therapies that modify the expression of proteins negatively affecting the function and health of the heart. The most famous example is the anti-PCSK9 therapy.

The case for restoring the PCSK9 gene

Discovered in 20032, the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is involved in low-density lipoprotein (LDL) homeostasis, and mutations within the gene result in high levels of LDLs and causes autosomal dominant hypercholesterolemia (ADH), a risk factor for coronary heart disease.

Initially, ADH was treated using LDL-lowering drugs3, predominantly statins, a family of drugs which lower the LDL concentration in the patient’s blood. This classic use of small molecule drugs was expanded by the development of antibody therapies, using anti-PCSK9 antibodies to modify its effect4-6.

Current research into treatments for elevated LDL levels explores the use of gene therapy to restore the function of the PCSK9 gene, thus restoring the LDL homeostasis in the patient.

Cell therapies & organ models to alleviate cardiovascular diseases

In other types of heart disease, including acute myocardial infarction, heart failure, and heart muscle or sinus node malfunction, it is the heart tissues, or the function thereof, which are affected.

Microfluidics systems engineered heart tissue (EHT), and the generation of the heart-on-a-chip technology have all proven very valuable in investigating potential treatments and modeling their outcomes7.

These technologies encourage higher confidence in the decision to pursue lead candidate drugs, in turn, improving clinical trial success rates.

Further evolution of the early EHT technologies is the exploration of induced pluripotent stem cells (iPSCs), hematopoietic stem cells (HSCs), or mesenchymal stem cells (MSCs). These types of cells are used to regenerate heart musculature function and the action potential of the sinus node.

Overview of cardiomyocyte culturing systems and heart models
The many trials of using stem cells have not been successful enough to produce any treatment schemes, despite strong efforts to make this approach work8. What stem cell research in the cardiac field has very successfully done, however, is to generate cardiac models to study the etiology and treatment of cardiac diseases.

When investigating cardiovascular diseases, iPSC-based cardiomyocytes, and organoid models (or mini-hearts) have also proven useful9,10. The mini-hearts are one of the later additions to the organoid model family.

Researchers have faced challenges in generating generate cardiac organoids (known as cardioids) as they consist of co-cultures of multiple tissues and must be self-organizing during formation. Stem cell-derived cardiac models are used for drug-discovery and for understanding the processes of cardiac development and function in the face of injury.

Turning to smartphones, AI & personalized care

A whole new approach to cardiac disease treatment includes early diagnostics, disease prevention and personalized care. With better tools for diagnosing anomalies very early in at-risk populations, physicians can administer early preventative treatment, rather than treat the disease once it is fully developed1.

Using such tools as wearables, smartphones and AI to analyze the gathered data to suggest and predict outcomes or actions, in addition to more traditional diagnostic tools, help improve both patient outcomes and quality of life.

Bringing control to cardiac culture systems

One of the initial and most basic challenges when developing a cardiac drug candidate or disease model, is maintaining tight control of the cell number both during culture system setup and testing. This especially applies in a co-culture system that must mature before testing protocols can take place, and where only a specific ratio of one cell type versus the other will result in a fully functional model.

But counting cardiomyocytes and supporting cell types is challenging. They grow on scaffolds of extracellular matrices, more elaborate cardiac-mimicking 3D structures or as aggregates. Dissociating these cells from the scaffold prior to counting is difficult; furthermore, counting on the intact scaffold is near impossible.

The NucleoCounter® NC-202™ automated cell counter provides robust cell count and viability using mammalian cells from complex samples. Whether the sample contains debris or red blood cells, the NC-202™ will give you unequaled reproducible data across samples, cell types, users, and instruments.

The automated cell counter features applications specifically for quantifying cells in suspension, adhered to flasks, grown as spheres or in organoid cultures. Also, our de-clumping reagents ensure a fast and consistent procedure for the separation of cells on aggregates and scaffolds.

With the robust NC-View™ software algorithm and unique Via2-Cassette™ sampling device, which eliminates human interference, you can focus on your experimental data collection and not worry about whether your initial cell culture setup was done correctly.

References

  1. R Young: Cardiology’s Challenge for the 2020s: Turning the Trend on Rising Mortality. Innovation. 2019; November.
  2. M Abifadel, M Varret, J-P Rabès, et al.: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6.
  3. P El Khoury, S Elbitar, Y Ghaleb et al.: PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies. Review Curr Atheroscler Rep. 2017 Oct 17;19(12):49.
  4. EA Stein, S Mellis, GD Yancopoulos, et al.: Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. Clinical Trial N Engl J Med. 2012 Mar 22;366(12):1108-18.
  5. MJ Koren, EM Roth, JM McKenney, et al.: Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis. Meta-Analysis Postgrad Med. 2015 Mar;127(2):125-32.
  6. PN Hopkins, J Defesche, SW Fouchier, et al.: Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet. 2015 Dec;8(6):823-31.
  7. K Andrysiak, J Stępniewski, J Dulak: Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research. Review Pflugers Arch. 2021 Jul;473(7):1061-1085.
  8. P Menasché: Cardiac cell therapy: Current status, challenges and perspectives. Archives of Cardiovascular Diseases. 2020; 113 (4), 285-292.
  9. M Seguret, E Vermersch, C Jouve, et al.: Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies. Review Biomedicines. 2021 May 18;9(5):563.
  10. P Hofbauer, SM Jahnel, N Papai, et al.: Cardioids reveal self-organizing principles of human cardiogenesis. Cell. 2021; 184 (12), 3299-3317.