Was Beethoven’s music inspired by genetic mutations for arrhythmia?


Many people believe Beethoven’s music came from his heart. Now there is scientific research that that may be literally true.

A team of researchers–a medical historian, cardiologist and musicologist from various universities–are proposing that Beethoven’s masterful compositions were influenced by his cardiac arrhythmia. Howell says the final movement in Beethoven’s Cavatina, Opus 130, a string quartet in b flat minor, gives some clues.

“That particular section and some of the other sections make us think that perhaps he was experiencing some kind of shortness of breath, that he wasn’t able to breathe because his heart was malfunctioning,” said Dr. Joel Howell is a professor of internal medicine at the University of Michigan School of Medicine, one of the team members.

The team further inferred that it’s likely Beethoven would be extra aware of his heartbeat, because he was deaf. Beethoven also offered this clue: “He talks about himself as a piece of music being ‘heavy of heart,’” said Howell.

Beethoven was not alone in his battle with arrhythmia, which scientists believe is inherited. About 5 percent of the U.S. population, some 14 million people, have arrhythmias. And sudden arrhythmic death syndrome (SADS) is one of the scariest medical phenomena that can run in a family, because it strikes unexpectedly, often against young people. Of roughly 350,000 people who die unexpectedly and suddenly due to problems in the heart, nearly 4,000 are under age 35, some of them teens or even children.

Looking at this from another angle, among high school athletes in the United States, 1 in 200,000 will die suddenly, usually with no prior symptoms. That’s because SADS typically is triggered by exertion, yet results from defects present since embryonic life.

When an autopsy can reveal no abnormality that could have led to the death, SADS is recorded, but rather than being a single, specific condition, it’s something that can result from any of several inherited, genetic abnormalities. Rather than affecting the anatomy of the heart, the abnormal genes affect what are called ion channels in the membranes surrounding the heart’s muscle cells, known as cardiomyocytes. Functioning as tiny doors, the ion channels control the movement of potassium, sodium, and calcium ions between the cell interior and the bloodstream.

Complex genetics

A large fraction of SADS cases result from a condition called long QT syndrome (LQTS). In most people with LQTS, the inherited abnormality involves two types of potassium channel. However, 14 different inherited forms of LQTS have been indentified, each with its own gene (some forms even with two genes). The genes have been located to specific regions of specific chromosomes, and different genetic forms of LQTS can involve channels for calcium and sodium in addition to the forms affecting potassium channels. This has major implications in terms of the needed treatments, even though they all forms of LQTS increase a person’s risk to the same, potentially fatal condition: cardiac arrhythmia.

This complexity has raised a major practical question, namely what to do with people whose ancestors or other relatives are known to have died suddenly at a young age. Does everybody with a genetic mutation for LQTS, or for another condition associated with SADS, actually carry a high risk of dying unexpectedly such that they require treatment? Until recently, the answer was a mystery, which was a major problem, since various treatments themselves may also carry risk. But, thanks to a new computational technique called a virtual human heart, cardiologists are beginning to get some answers. As it has turned out with so many genetic phenomena, here too the same mutation does not always affect different people with the same severity.

Arrhythmia: Heart beating out of synch

A normal heart pumps blood efficiently, because all of the cardiomyocytes beat in unison. The term arrhythmia refers to an abnormal heartbeat, but there are many different types of arrhythmia, and many types are not dangerous. However, people with LQTS genes are prone specifically to types of arrhythmia that can deteriorate into a state called ventricular fibrillation in which the beating of cardiomyocytes is entirely unsynchronized, so no blood is pumped. This is rapidly fatal, unless the person is treated immediately with cardioversion (electrical stimulation to the heart) and various drugs. People at high risk for fatal arrhythmias can be implanted with automatic cardioversion devices, but as noted earlier there has always been uncertainly about whether everybody with a gene for an SADS causing condition is really at risk.

Virtual hearts beating down under

A virtual heart is a simulation of hearts beating on a super computer. Using such powerful computational approaches, researchers at Australia’s Victor Change Cardiac Research Institute in Sydney, have been able to demonstrate that not everyone carrying a gene for LQTS needs preventive treatment, but they do all need to be checked with electrocardiography (EKG). The term “long QT” in the LQTS acronym actually refers to a very specific phenomenon that’s easily recognized on EKG. In electrocardiography, the letters P-Q-R-S-T stand for different parts of an electrical wave that shows up in a certain shape, due to electrical activity moving through the heart muscle.

On first seeing an EKG readout, the first thing a physician does is check the distances between the various peaks and valleys, which provides not only the heart rate, but also clues about possible problems. While the segment known as the QRS represents the electrical activity that causes the ventricles to beat, the “T Wave” (which follows the S) represents the recovery of the ventricles, which allows them to beat the next time. If more than a certain amount of time passes between the Q wave and the T wave, certain regions of the heart muscle will not be ready on time for the next contraction, and this is what triggers the dangerous arrhythmia. There also is a telltale notch on the T wave that acts as a clue.

While this physiology has been understood for decades, the Australian supercomputing study has linked the physiology to the underlying genetics.

“For the past 30 years, that notched t-wave has been in the diagnostic criteria but nobody’s known what’s caused it,” says Adam Hill, leader of the study. “We show what causes it.”

This finding, in turn, has some very practical implications. If you have a gene for LQTS, you’re in danger only if there actually is a prolonged QT interval. In other words, suppose that there are two siblings, both children of a parent who dies suddenly at a young age, and suppose that both have an LQTS gene, yet only one of them actually has a prolonged QT interval. Only the latter one needs treatment. On the other hand, it also means that the genetic screening is vital, since it shows who must be checked by EKG. But from a genetic standpoint, it also means the risk comes from the gene plus something else. In other words, either the genes react in unknown ways with the environment, or there are some unknown other genes involved. Either way, the situation is very complex –just like every other new discovery in genetics to date.

David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

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