Biological pacemaker
Encyclopedia
The heart
is endowed with specialized excitatory and conducting cells
that are responsible for the generation and conduction of rhythmic impulses and contractions
throughout the heart. If these cells are damaged by disease
, the implantation of an artificial pacemaker
becomes necessary.
s several limitations and problems have emerged during the past decades such as electrode
fracture
or damage to insulation, infection
, re-operations for battery
exchange and venous thrombosis
. The need for an alternative is most obvious in children including premature newborn babies
where size mismatch and the fact that pacemaker leads do not grow with children are a problem.
The first successful experiment with biological pacemakers was carried out by Arjang Ruhparwar's group at Hannover Medical School
in Germany using transplanted fetal heart muscle cells, first introduced at the scientific sessions of the American Heart Association
in Anaheim
in 2001 and published in 2002. A few months later, Eduardo Marban's group from Johns Hopkins University
published the first successful gene-therapeutic approach towards the generation of pacemaking activity in otherwise non-pacemaking adult cardiomyocytes using a guinea pig
model. The investigators postulated latent pacemaker capability in normal heart muscle
cells. This potential ability is suppressed by the inward-rectifier
potassium
current Ik1 encoded by the gene
Kir2 which is not expressed in pacemaker cells
. By specific inhibition of Ik1 below a certain level, spontaneous activity of cardiomyocytes was observed with resemblance to the action potential pattern of genuine pacemaker cells. Meanwhile other genes and cells have been discovered, including heart muscle cells derived from embryonic stem cell
s, "HCN" genes which encode the wild type
pacemaker current I(f). Michael Rosen's group demonstrated that transplantation of HCN2-transfected human mesenchymal stem cell
s (hMSCs) leads to expression of functional HCN2 channels in vitro
and in vivo
, mimicking overexpression of HCN2 genes in cardiac myocyte
s. Again, Ruhparwar's group demonstrated that by injection of the "Adenylate Cyclase" gene into the heart muscle a biological cardiac pacemaker can be created).
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
is endowed with specialized excitatory and conducting cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
that are responsible for the generation and conduction of rhythmic impulses and contractions
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
throughout the heart. If these cells are damaged by disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, the implantation of an artificial pacemaker
Artificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
becomes necessary.
Research
Despite the successes of artificial pacemakerArtificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
s several limitations and problems have emerged during the past decades such as electrode
Electrode
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
fracture
Fracture
A fracture is the separation of an object or material into two, or more, pieces under the action of stress.The word fracture is often applied to bones of living creatures , or to crystals or crystalline materials, such as gemstones or metal...
or damage to insulation, infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, re-operations for battery
Battery (electricity)
An electrical battery is one or more electrochemical cells that convert stored chemical energy into electrical energy. Since the invention of the first battery in 1800 by Alessandro Volta and especially since the technically improved Daniell cell in 1836, batteries have become a common power...
exchange and venous thrombosis
Venous thrombosis
A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. (Thrombosis is a medical term for blood clotting (Haemostasis) occurring in the wrong place, i.e...
. The need for an alternative is most obvious in children including premature newborn babies
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
where size mismatch and the fact that pacemaker leads do not grow with children are a problem.
The first successful experiment with biological pacemakers was carried out by Arjang Ruhparwar's group at Hannover Medical School
Hannover Medical School
The Hannover Medical School , founded in 1965, is a university medical centre in Germany, part of a regional medical network.-International:...
in Germany using transplanted fetal heart muscle cells, first introduced at the scientific sessions of the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
in Anaheim
Anaheim, California
Anaheim is a city in Orange County, California. As of the 2010 United States Census, the city population was about 365,463, making it the most populated city in Orange County, the 10th most-populated city in California, and ranked 54th in the United States...
in 2001 and published in 2002. A few months later, Eduardo Marban's group from Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
published the first successful gene-therapeutic approach towards the generation of pacemaking activity in otherwise non-pacemaking adult cardiomyocytes using a guinea pig
Guinea pig
The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
model. The investigators postulated latent pacemaker capability in normal heart muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
cells. This potential ability is suppressed by the inward-rectifier
Rectifier
A rectifier is an electrical device that converts alternating current , which periodically reverses direction, to direct current , which flows in only one direction. The process is known as rectification...
potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
current Ik1 encoded by the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
Kir2 which is not expressed in pacemaker cells
Cardiac pacemaker
right|thumb|350px|Image showing the cardiac pacemaker which is the SA nodeThe contraction of heart muscle in all animals with hearts is initiated by chemical impulses. The rate at which these impulses fire controls the heart rate...
. By specific inhibition of Ik1 below a certain level, spontaneous activity of cardiomyocytes was observed with resemblance to the action potential pattern of genuine pacemaker cells. Meanwhile other genes and cells have been discovered, including heart muscle cells derived from embryonic stem cell
Embryonic stem cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
s, "HCN" genes which encode the wild type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
pacemaker current I(f). Michael Rosen's group demonstrated that transplantation of HCN2-transfected human mesenchymal stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s (hMSCs) leads to expression of functional HCN2 channels in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, mimicking overexpression of HCN2 genes in cardiac myocyte
Myocyte
A myocyte is the type of cell found in muscles. They arise from myoblasts.Each myocyte contains myofibrils, which are long, long chains of sarcomeres, the contractile units of the cell....
s. Again, Ruhparwar's group demonstrated that by injection of the "Adenylate Cyclase" gene into the heart muscle a biological cardiac pacemaker can be created).