Heart disease genetics
This essay was written by Leon D’Cruz and was first published in the 2005 Mill Hill Essays.
No other organ evokes so much passion and emotion as the heart. In almost all cultures, the heart is spoken of as the vessel containing our moral or spiritual values and sometimes even the very seat of the human soul. Thus, when a disease affects the heart especially in the young or in people who are reasonably fit, it isn’t surprising that the immediate reaction of society is one of shock and disbelief.
In June of 2003, football fans around the world were shocked to see Marc Vivien-Fo, the Cameroonian footballer who played for Manchester City F.C., suddenly fall to the ground for no apparent reason in the seventy-second minute of the match against Colombia. The cause of death was later determined to be Hypertrophic Cardiomyopathy – a disease of the heart muscle. This was not an isolated case; there have been numerous reports of other athletes succumbing to this heart condition. Since participation in sports is generally thought to improve and maintain the cardiovascular fitness of an individual, it is intriguing when intense sporting activity actually causes the death of someone and when that death is linked in some way to the heart.
Hypertrophy means an increase in the size of a tissue or organ due to the enlargement of existing cells. Thus, Hypertrophic Cardiomyopathy (HCM) is a disease that causes the muscular tissue of the heart to become thicker, causing the heart to grow to an abnormal size. It is an inheritable condition passed from parents down to their children through their genes. In the UK the disease affects one person in every five hundred. Scientists have identified mutations in ten different genes that code for proteins that form the heart’s motor-like mechanism. This mechanism allows the muscles of the heart to beat and thereby pump blood around the body. Mutations in one or more of these genes can cause the blood-pumping action of the heart to weaken, so that the volume of blood pumped decreases and blood pressure falls.
Low blood pressure also affects the performance of the kidneys which normally act to filter out unwanted substances from blood, a bit like a chemical sieve. When blood pressure is reduced, filtering is impaired and the impurities increase in concentration. As a result an enzyme called renin is released, thereby activating the Renin-Angiotensin System (RAS). The RAS is a network of interacting proteins which, through a variety of effects, helps to regulate blood pressure and blood volume. The first stage of the pathway is the release of renin. Renin then transforms an inactive substance into a protein called angiotensin I (AT1), and another enzyme converts this into a hormone called angiotensin II (AT2). The second enzyme is called angiotensinconverting enzyme (ACE). The principal effect of angiotensin II is to make blood vessels constrict, thereby causing blood pressure to increase. The RAS thus counterbalances the blood pressure reduction caused by HCM, and restores the proper functioning of the kidneys. However, the increase in blood pressure also causes the heart muscle cells to increase in size, through an as yet unknown mechanism and thereby increase the volume of blood pumped by the heart.
It has been observed that the degree of HCM in an individual is affected by their particular variant of the gene that codes for the ACE protein but there are other proteins involved in hypertrophy of the heart, one of which is called NFkappaB. This is what is known as a transcription factor, and its function is to switch on genes so that they begin to make their protein. It does this by binding to a region of the gene called the promoter. Normally, NF-kappaB regulates the production of proteins that are involved in inflammation, immune responses, cell survival and cell division. NF-kappaB plays a critical role in the hypertrophic growth of heart muscle cells which become enlarged when NFkappaB levels increase. It has also been noted that mechanical stress on heart muscle cells, such as that caused by HCM, induces the production of NFkappaB.
Muscle cells account for a third of the total number of cells in the human heart, along with nerve cells and cells forming the supporting structure, called connective tissue. Under the microscope, normal heart muscle cells are neatly arranged like stacks of bricks that make up a wall. This neat layering of cells in the heart muscle is important since it allows tiny electrical currents that are needed to stimulate the heart’s pumping action to spread around the heart in an orderly way. In HCM, new layers of cells are laid on the existing matrix in a haphazard fashion. It is thought that the connective tissue in the heart, formed mainly from cells called fibroblasts, acts as an insulator for the electrical currents conveyed by the heart’s nerve cells. If the neat layerings of cells are disturbed for some reason then the disordered layer of connective tissue would present obstacles for the conduction of electrical pulses, and the rhythmical pumping motion of the heart would be affected. However, this idea has recently been questioned, as studies in mice carrying a mutation that causes HCM have shown that some mice showing disarray in heart muscle cells did not experience variations in heartbeat, known as arrhythmia. This contrasts with observations in human patients and it may be that the increased susceptibility of a human patient to heart arrhythmia is due to the effects brought about by the hypertrophy itself. These are interesting findings, which will surely trigger more research into the actual causes of the hypertrophy of the cardiac muscle.
One of the important features of HCM is that the disease may lie dormant for years without the patient exhibiting any disability, until a sudden cardiac arrest leads to death. Frequently, patients with the condition show no signs of the disease, even when medically examined, until it is too late to do anything. However, when an unexpected sudden death from a heart attack occurs in a seemingly young and fit person then other members of the family are tested for mutations in any one of the ten genes of the heart muscle. Genetic testing has proved to be a very powerful tool to identify the members of a family who might be at risk of a heart attack as a result of HCM, even though no signs of the disease are detectable using standard clinical tools such as echocardiography. These family members can be placed under the care and surveillance of expert clinical teams and their overall health regularly monitored.
There is a further perplexing issue surrounding HCM, the phenomenon of incomplete genetic penetrance. Penetrance is a term used in genetics that describes the extent to which the effects of a gene are observed. The effects of a highly penetrant gene, for example, will be seen almost regardless of any other characteristics, whereas a gene with low penetrance will only sometimes produce the symptom or trait with which it is associated. One genetic study identified a patient with HCM who had a mutation in a particular heart muscle gene. The diagnosis was made when the patient was in her early twenties and she suffered frequent fainting spells (a common symptom of HCM), palpitations and chest pains. Over a period of six years, the patient showed progressive increase in the thickness of the left ventricular wall. She also had the ECG pattern and other abnormalities characteristic of the disease. However, she had an older sibling who carried exactly the same mutation but who was clinically normal and had an apparently healthy life. Thus, an individual may carry the gene but not actually have the disease. The key to identifying causative inherited disease genes is to find a large family where several members display clear symptoms of the disease. Finding a causative gene in the entire human chromosome can be likened to finding a needle in a haystack, but the search for disease-causing genes continues, not only in HCM, since knowledge of the genetic basis of the disease can help scientists to identify the defects in the biological functions that result in disease. Once these defects are identified, then the search for a therapy to correct them can begin, and in due course scientific advances can benefit patients. The scientific discovery process is dependent on the use of the knowledge accumulated by our predecessors, as Isaac Newton said, “If I have seen further it is by standing on the shoulders of Giants“. Each discovery, however fundamental it is, will eventually help in our understanding of the mechanisms of these terrible heart diseases.