Basics
Description
- Programmed cell death that is a tightly regulated energy dependent method, in which a specific genetic process leads to activation of a molecular cascade that then causes the destruction of DNA.
- Important aspect of normal organ development, as well as reaction to cell injury
- It was once thought that terminally differentiated cell lines such as cardiac myocytes did not possess the genetic machinery to undergo apoptosis; however, recent evidence suggests that apoptosis may play an essential role in cardiovascular diseases.
- Cardiac myocytes undergoing apoptosis have been identified in tissue samples from patients with MI, diabetic cardiomyopathy, and end-stage heart failure.
- Apoptosis vs. necrosis:
- Apoptosis:
- Genetically driven cell death
- Cell membrane remains intact
- No inflammatory response
- Segregation of the nuclear chromatin into masses that abut nuclear envelope
- Cell shrinkage
- Condensation of the cytoplasm
- Nuclear fragmentation than blebbing forming apoptotic bodies
- Phagocytosis by surrounding cells
- Necrosis:
- Accidental form of cell death caused by injury to the cell: Ischemia or toxins
- Cell membrane rupture
- Inflammation present
Pathophysiology
Molecular basis of cardiac apoptotic pathways:
- At least 2 pathways are known to exist: Intrinsic and extrinsic. Cross-talk exists between the 2 pathways.
- Both pathways involve the activation of caspases, which are a family of proteases that cleave target proteins resulting in cell death.
- In the myocyte, the target proteins include actin, myosin, tropomyosin, and troponin.
- Further regulation takes place through complex molecular interactions involving multiple proteins including: Bcl-2 family, BH3, p53, IGF-1, inhibitor of apoptosis proteins (IAPs), and apoptosis regulator with caspase recruitment domain (ARC).
- Intrinsic pathway:
- Cellular stresses such as hypoxia, ischemia, and oxidative stress activate the intrinsic pathway of the myocyte.
- Cellular stresses induce the mitochondrial permeability transition pore (MPTP) to open and release cytochrome c and other proteins, including apoptosis-inducing factor (AIF), into the cytosol.
- Cytochrome c activates caspase-9 and caspace-3 resulting in apoptosis.
- Extrinsic pathway:
- Also called death receptor pathway
- Death receptors (Fas/CD95 and TRF-alpha) are activated by ligands.
- Death-inducing signaling complex (DISC) is activated.
- DISC activates caspace-8 and caspace-3 resulting in apoptosis.
- Other pathways:
- Other less well-studied pathways involve the endoplasmic reticulum and caspase-12.
Etiology
Evidence of apoptosis in cardiovascular diseases:
- Ischemic heart disease:
- Studies have demonstrated that apoptosis is present with ischemic heart disease in both the animal and human models.
- Interestingly, in rat coronary occlusion model a reduction in infarct size and ischemic area were smaller in rats treated with a caspase inhibitor.
- Heart failure:
- It has been proposed that the progressive LV dysfunction that occurs in heart failure may be secondary to a loss in myocytes from apoptosis.
- Supporting this argument are numerous animal and human studies showing evidence of apoptosis in heart failure.
- Hypertrophy:
- The process in which there is a transition from a compensated hypertrophic heart to decompensated heart failure is not completely understood.
- Although not much evidence yet exists to support apoptosis as a cause of this transition, it has been proposed that hypertrophy may make the hypertrophic myocyte more susceptible to apoptosis.
Treatment
- Possible target antiapoptotic therapies:
- Inhibitors of rennin-angiotensin- aldosterone system:
- The benefits of inhibiting the of rennin-angiotensin- aldosterone system in heart failure patients may be partly explained by their antiapoptotic activity.
- ACE inhibitors' antiapoptotic effect thought to act via effect on endothelial nitric oxide
- ARBs block the proapoptotic AT1-mediated signals.
- β-Blockers:
- Heart failure is associated with a decrease in antiapoptotic proteins and an increase in proapoptotic proteins. β-Blockers have been shown to prevent these changes
- Calcium channel blockers:
- Specifically, amlodipine has been shown in vitro to attenuate proapoptotic effects; although these agents are ideal for heart failure patients given the adrenergic activation.
- Statins:
- Acts via improving endothelial NOS synthase dysfunction
- Immunomodulating agents (TNF-α inhibitors)
- Caspase inhibitors:
- Caspases are known to be crucial to the apoptotic pathway and thus are a natural target.
- Endonucleases:
- Endonucleases provoke DNA strand breaks and are in the final process of the apoptotic pathway.
- Aurintricarboxylic acid is an inhibitor of endonucleases and, in animal models, has been shown to inhibit apoptosis.
- Ca sensitizers (levosimendan)
- Recombinant natriuretic peptides
- Erythropoietin
- Insulin-like growth factor-1 (IGF-1)
- Antioxidants
- Nonpharmaceutical antiapoptotic interventions: Exercise, cardiac resynchronization, LV assist device
- Limitation of antiapoptotic therapies;
- Apoptosis plays a necessary role in cell regulation, specifically in cancer. An important obstacle to overcome in antiapoptotic therapy would be to selectively delver treatment to the organ system of interest and avoid adverse effects on other organ systems.
Additional Reading
1
Colucci WS, Braunwald E.
Pathophysiology of Heart Failure. In: Zipe D, Braundwald's Heart Disease, 7th ed.Philadelphia: Elsevier Saunders, 2005:509-535. 2
Kang PM, Yue P, Izumo S.
New insights into the role of apoptosis in cardiovascular disease. Circulation. 2002;66:1-9. [View Abstract] 3
Lee Y, Gustafosson B.
Role of apoptosis in cardiovascular disease. Apoptosis. 2009;14:536-548. [View Abstract] 4
Olivetti G, Abbi R, Quaini F. Apoptosis in the failing human heart. N Engl J Med. 1997;336:1131-1141. [View Abstract] 5
Sabbah HN, Sharov VG, Goldstein S.
Cell death, tissue hypoxia and the progression of heart failure. Heart Fail Rev. 2000;5:131-138. [View Abstract] 6
Van Empel VP, Bertrand AT, Hofstra L. Myocyte apoptosis in heart failure. Cardiovasc Res. 2005;67:21-29. [View Abstract] 7
Yaoita H, Maruyama Y.
Interventions for apoptosis in cardiomyopathy. Heart Fail Rev. 2008;13:181-191. [View Abstract] 8
Yaoita H, Ogawa K, Maehara K. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation. 1998;97:276-281. [View Abstract]
Codes
ICD9
- 414.9 Chronic ischemic heart disease, unspecified
- 428.9 Heart failure, unspecified
SNOMED
- 414545008 ischemic heart disease (disorder)
- 84114007 heart failure (disorder)
Clinical Pearls
- Apoptosis is programmed cell death, a tightly regulated, energy-dependent process in which a specific genetic process leads to activation of a molecular cascade that then causes the destruction of DNA.
- Although the extent of the role of apoptosis in cardiovascular disease has not yet been elicited, both human and animal models have shown that apoptosis does play a role in ischemia, heart failure, and hypertrophy.
- Potential antiapoptotic targets include: neurohormonal axis, caspases, endonucleases, statins, calcium channel blockers, calcium sensitizers, recombinant natriuretic peptides, erythropoietin, immunomodulating agents, insulin-like growth factor-1 (IGF-1), antioxidants, and nonpharmaceutical interventions.