The human heart is a fine-tuned organ that pumps blood to the lungs to pick up oxygen, and then throughout the body to deliver the oxygen to all of its tissues. If the heart stops pumping, or a blockage forms in the arteries, oxygenated blood will not reach the brain and other important organs, and a person can die within minutes.
A variety of risk factors such as high blood pressure, elevated blood cholesterol levels, smoking, obesity, diabetes, and unhealthy lifestyle can have a negative impact on normal heart function and may lead to a development of cardiovascular disease.
Cardiovascular disease is a general term for a broad group of medical problems affecting the heart and blood vessels. These diseases are the leading cause of death worldwide. It is estimated that 17 million people die every year from cardiovascular diseases and 85% of these deaths are due to heart attack and stroke.
The number of people dying from cardiovascular disease is on the rise in almost every country around the globe. Most heart diseases can be prevented with a healthy lifestyle, but despite this, it is still the most common disease among people in the world. The higher the number of people suffering from cardiovascular disease, the higher the healthcare costs. This puts a huge economic and social burden on our society and it reflects an urgent need for measures aimed at reducing cardiovascular risks in order to combat this global burden.
Getting to the heart of the matter
Cardiac muscle tissue exists only in the heart and is responsible for keeping the heart pumping and relaxing normally. The heart tissue consists of 3 billion heart muscle cells that squeeze (contract) in coordination during each heartbeat with enough force and blood to supply the metabolic demands of the entire body. To make sure that each heart muscle cell contracts at the right moment, the heart uses an electrical signal that moves from cell to cell.
Cardiac muscle contraction occurs via the sliding of actin thin filaments along myosin thick filaments. This process is powered by adenosine triphosphate (ATP) which is hydrolysed to provide the energy for myosin to bind to a new position on actin. Binding of a new ATP molecule to myosin releases the myosin from actin, and myosin hydrolyzes ATP to repeat the process. If a new ATP molecule is not available, myosin remains bound to actin indefinitely, causing stiffness of the muscle. Another key cofactor in cardiac muscle contraction is calcium. Calcium ions are required by two proteins, troponin and tropomyosin, located on the actin filament. They regulate muscle contraction by blocking the binding of myosin to actin. After the binding of a calcium ion to troponin, it changes the conformational state of tropomyosin and moves the tropomyosin away from the actin, thus exposing the myosin-binding site on the actin filament which allows ATP to bind to myosin.
Thin filaments are composed primarily of actin molecules arranged in a double helix. The regulatory proteins tropomyosin and troponin are bound to actin in the molar ratio 1:1:7 respectively. Tropomyosin is a long α-helical coiled-coil protein that binds in the groove between two actin strands. Adjacent tropomyosin molecules interact in a head-tail manner, forming continuous strands that lie along the actin filament. Each tropomyosin repeating region (approximately 38 nm long) has one troponin molecule associated with it.
Thin and thick filaments in cardiac muscle (Image credit: https://www.sigmaaldrich.com/GB/en/technical-documents/technical-article/research-and-disease-areas/cell-signaling/myosin).
Troponin has a long tail and a globular core domain. It consists of three different subunits � troponin C (calcium ion-binding subunit), troponin I (the actin-myosin interaction inhibitory subunit), and troponin T (the tropomyosin-binding subunit anchoring the troponin complex to the thin filament).
Three different subunits of cardiac troponin complex in the calcium saturated form (PDB:1J1E)
Troponin C (TnC) is composed of N-terminal and C-terminal globular domains connected by a flexible linker. Each globular domain has two calcium-binding sites consisting of a calcium-coordinating loop rich in acidic residues and two α-helical segments. Interestingly, only two calcium binding sites (III and IV in the C-terminus) display high affinity towards calcium ions. In contrast, there is only one functional low-affinity calcium-binding site (II) in the N terminus. Calcium plays a dual role in TnC � it stabilises the structural C-terminal domain via two high-affinity binding sites, as well as activating the regulatory N-terminal domain via a single low-affinity binding site which acts as a calcium sensor.
The role of troponin I (TnI) is to inhibit the contractile interaction between myosin and actin in a resting muscle. TnI binds to TnC, forms a coil-coiled structure with TnT, and its C-terminal region interacts with actin-tropomyosin at low calcium concentration. When calcium binds to TnC, conformational changes occur in TnI leading to its dislocation. Afterwards, tropomyosin leaves the actin-myosin binding site, resulting in muscle contraction.
Troponin T (TnT) facilitates binding to tropomyosin and helps position it on actin. It is not directly involved in the calcium regulation but its presence is important for this process to take place.
Cardiac troponins T and I are used as markers to detect injury to the cardiac muscle, especially heart attack. Normally, troponin levels are close to undetectable in the blood. When the heart muscle is damaged, troponins are released from heart cells into the bloodstream. As heart damage progresses or there is more damage to the heart, a greater amount of troponin T and troponin I may be detected in the blood.
The regulation of cardiac muscle contraction by troponin has been a fascinating study area since its discovery almost 60 years ago. Its high sensitivity and specificity make it a very useful biomarker in the diagnosis of heart muscle damage. In recent times, cardiac troponin has become important not only for diagnosis but also for understanding the pathogenesis and treatment of cardiac diseases.
Did you know?
1. According to a study published in 2019, France, Peru, and Japan are the countries with the lowest heart disease death rates. On the contrary, Tajikistan had the highest number of heart disease deaths, followed by Azerbaijan and Uzbekistan.
2. Calcium channel blockers are commonly prescribed to treat high blood pressure. They work by slowing the influx of calcium into the cells of the heart. As a result, the heart doesn’t squeeze so hard and blood pressure lowers.
3. Heart cancer is very rare because heart cells stop dividing early in life.
Romana Gáborová
About the artwork
Sofia Biggs, aged 16, is a student at The Leys School in Cambridge. She enjoys printing and creating art based on the human body. In her spare time, she loves to listen to music and socialise with friends and family.
View the artwork in the .
Troponin structure mentioned in this article
PDB ID 1J1E
Link to troponin C at the PDBe-KB protein pages
Link to troponin I at the PDBe-KB protein pages
Link to troponin T at the PDBe-KB protein pages
Sources
