Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine
Author and Curator: Larry H Bernstein, MD, FCAP
and
Curator: Aviva Lev-Ari, PhD, RN
This document is entirely devoted to medical and surgical therapies that have made huge strides in
- simplification of interventional procedures,
- reduced complexity, resulting in procedures previously requiring surgery are now done, circumstances permitting, by medical intervention.
This revolution in cardiovascular interventional therapy is regenerative medicine. It is regenerative because it is largely driven by
- the introduction into the impaired vasculature of an induced pleuripotent cell, called a stem cell, although
- the level of differentiation may not be a most primitive cell line.
There is also a very closely aligned development in cell biology that extends beyond and including vascular regeneration that is called synthetic biology. These developments have occurred at an accelerated rate in the last 15 years. The methods of interventional cardiology were already well developed in the mid 1980s. This was at the peak of cardiothoracic bypass surgery.
Research on the endothelial cell,
- endothelial cell proliferation,
- shear flow in small arteries, especially at branch points, and
- endothelial-platelet interactions
led to insights about plaque formation and vessel thrombosis.
Much was learned in biomechanics about the shear flow stresses on the luminal surface of the vasculature, and there was also
- the concomitant discovery of nitric oxide,
- oxidative stress, and
- the isoenzymes of nitric oxide synthase (eNOS, iNOS, and nNOS).
It became a fundamental tenet of vascular biology that
- atherogenesis is a maladjustment to oxidative stress not only through genetic, but also
- non-genetic nutritional factors that could be related to the balance of omega (ω)-3 and omega (ω)-6 fatty acids,
- a pro-inflammatory state that elicits inflammatory cytokines, such as, interleukin-6 (IL6) and c-reactive protein(CRP),
- insulin resistance with excess carbohydrate associated with type 2 diabetes and beta (β) cell stress,
- excess trans- and saturated fats, and perhaps
- the now plausible colonic microbial population of the gastrointestinal tract (GIT).
There is also an association of abdominal adiposity,
- including the visceral peritoneum, with both T2DM and with arteriosclerotic vessel disease,
- which is presenting at a young age, and has ties to
- the effects of an adipokine, adiponectin.
Much important work has already been discussed in the domain of cardiac catheterization and research done to
- prevent atheroembolization.and beyond that,
- research done to implant an endothelial growth matrix.
Even then, dramatic work had already been done on
- the platelet structure and metabolism, and
- this has transformed our knowledge of platelet biology.
The coagulation process has been discussed in detailed in a previous document. The result was the development of a
- new class of platelet aggregation inhibitors designed to block the activation of protein on the platelet surface that
- is critical in the coagulation cascade.
In addition, the term long used to describe atherosclerosis, atheroma notwithstanding, is “hardening of the arteries”. This is particularly notable with respect to mid-size arteries and arterioles that feed the heart and kidneys. Whether it is preceded by or develops concurrently with chronic renal insufficiency and lowered glomerular filtration rate is perhaps arguable. However, there is now a body of evidence that points to
- a change in the vascular muscularis and vessel stiffness, in addition to the endothelial features already mentioned.
This has provided a basis for
- targeted pharmaceutical intervention, and
- reduction in salt intake.
So we have a group of metabolic disorders, which may alone or in combination,
- lead to and be associated with the long term effects of cardiovascular disease, including
- congestive heart failure.
This has been classically broken down into forward and backward failure,
- depending on decrease outflow through the aorta (ejection fraction), or
- decreased venous return through the vena cava,
which involves increased pulmonary vascular resistance and decreased return into the left atrium.
This also has ties to several causes, which may be cardiac or vascular. This document, as the previous, has four pats. They are broadly:
- Stem Cells in Cardiovascular Diseases
- Regenerative Cell and Molecular Biology
- Therapeutics Levels In Molecular Cardiology
- Research Proposals for Endogenous Augmentation of circulating Endothelial Progenitor Cells (cEPCs)
As in the previous section, we start with the biology of the stem cell and the degeneration in cardiovascular diseases, then proceed to regeneration, then therapeutics, and finally – proposals for augmenting therapy with circulating endogenous endothelial progenitor cells (cEPCs).
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