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Early discoveries
Like the physiology of blood circulation any discussion of modern heart physiology must start with William Harvey (1578-1657). In De Motu Cordis, Harvey demonstrated that the heart is a muscular pump and that blood circulates in one direction. He was the first person to demonstrate the true function of the heart valves, showing that they enforce one‑way blood flow. Harvey’s experiments proved that the valves open and close due to pressure differences and prevent backflow.
Richard Lower (1631-1691) published in 1669 a remarkable treatise on the heart, which added much of importance to Harvey’s account. It gave a modern description of the arrangement of the muscular layers of the heart, definite proof of the myogenic nature of the heartbeat, and an estimation of the heart’s output and of the rapidity of the blood flow. Lower narrowly missed anticipating the Webers’ discovery of vagal inhibition.
Stephen Hales (1677–1761) performed the first direct blood‑pressure measurements in living animals. He quantified stroke volume and cardiac output and showed that valve behaviour is governed by pressure gradients. His work was extended by Daniel Bernouilli (1700-1782) and Daniel Passavant (1722 – 1799) who calculated the heart work correctly by multiplying stroke volume with vertical displacement to arrive at realistic numbers.
Albrecht von Haller (1708–1777) Distinguished between nerve excitability and muscle contractility. He clarified that the heart’s rhythmicity is intrinsic to cardiac muscle. This shifted the notion of the heart as an externally controlled pump to an autonomous organ. But he thought that blood moves as a bulk fluid after each heartbeat, a notion that was correct by the Weber brothers. The mercury manometer was introduced by Jean L. M. Poiseuille (1799-1869).
Intrinsic excitability of the heart
Following on from Haller’s work who showed that a heart continued to beat even when all nerves were disconnected from it, Luigi Galvani showed in 1791 that a frog’s heart—removed from the body—continued to contract for a time due to its intrinsic excitability. Friedrich W. Bidder (1810-1894), a pupil of Müller, discovered that cardiac muscle fibers branch and intercommunicate thus forming a continuum. Jan E. Purkinje (1787-1869) described the presence of the distinctive fibers that are named after him (1846). Purkinje fibers are specialized, electrically excitable cardiac cells which are seated just beneath the endocardium in the subendocardial layer of both ventricles. They are a distinct subtype of modified cardiomyocytes adapted for conduction rather than contraction. In 1839, German physiologist Robert Remak (1815-1865), a pupil of Johannes Müller, discovered the presence of groups of ganglion cells in the sinus venosus of the frog, comparable to similar ganglia in the respiratory center that were thought to regulate the muscles of respiration automatically. Müller suggested that these sinus venosus cells initiated and perpetuated the heartbeat in response to sympathetic stimulation. This location was further supported by the 1852 studies of Hermann F. Stannius (1808-1883), who tied a ligature around the sinoatrial junction of a frog’s heart, causing standstill of the atria and ventricle while the sinus portion still contracted.
The subject of the exact site of origin of the heartbeat dominated late nineteenth-century cardiac physiology. In 1872, Luigi Luciani also found evidence that the rhythmic activity of the frog heart was most highly developed in the vena cava and sinus venosus. Hugo Kronecker (1839-1914) “the soul of the Ludwig’s Institute in Leipzig,” showed that the frog’s heart is refractory to stimulation during systole. Ludwig was the first to successfully keep an organ alive outside the body.
Walter H. Gaskell (1847-1914) introduced the suspension method for recording cardiac contractions in frogs and turtles. Largely through results obtained by this simple method during the years 1882 to 1887 he concluded that cardiac beats depend on the rhythmic release of impulses by muscle cells—not ganglion cells—in the large veins or sinus venosus. He found that the contraction wave spreads over atria and ventricle by muscular tissue at rates of speed which vary in different regions; and that their passage from atrium to ventricle may be impeded or prevented by mechanical compression (heart block, A-V block). A conducting bundle between the atrium and the ventricle was found by Wilhelm His, Jr (1863-1934) in 1893 at the University of Leipzig, but he did not show that it conducted the impulse.
In 1906, Sunao Tawara (1873-1952), a young Japanese anatomist working under Ludwig Aschoff in Marburg, Germany, published The Conduction System of the Mammalian Heart. Tawara found a “complex Knoten” (the atrioventricular (AV) node) of tissue at the proximal end of the His bundle. He concluded that this was the inception of an electrical conducting system which continued from the AV node through the bundle of His, divided into the right and left bundle branches, and terminated as the Purkinje fibres. Tawara was the first to appreciate that Purkinje fibres were conducting tissue which rapidly delivered the impulse to the ventricular apex so that contraction would spread from apex to base.
However, the specific structure responsible for initiating the heartbeat had not been identified.
In 1907 Arthur Keith (1866-1955) and Martin Flack (1882-1931) provided anatomical identification of a distinct cluster of specialized tissue at the junction of the superior vena cava and right atrium. They interpreted it as the site of origin of the heartbeat, the dominant pacemaker. Using a string galvanometer Thomas Lewis (1881-1945) confirmed that the region around the Sinus node initiated the excitation wave across the heart.
These discoveries resolved the long-running myogenic vs neurogenic debate by showing that the heartbeat originates in specialized muscle tissue, not nerves.
Willem Einthoven (1860–1927, Nobel Prize 1924) invented the electrocardiogram (ECG) and mapped the electrical activity underlying cardiac contraction. Before Einthoven’s time, it was known that the beating of the heart produced electrical currents, but the instruments of the time could not accurately measure this phenomenon without placing electrodes directly on the heart. Beginning in 1901, Einthoven completed a series of prototypes of a string galvanometer. This device used a very thin filament of conductive wire passing between very strong electromagnets. When a current passed through the filament, the magnetic field created by the current would cause the string to move. A light shining on the string would cast a shadow on a moving roll of photographic paper, thus forming a continuous curve showing the movement of the string. This device increased the sensitivity so that the electrical activity of the heart could be measured despite from the outside. Building on this research Carl Wiggers (1883–1963) defined the phases of systole and diastole with precision. He integrated pressure, flow, and electrical activity into a unified model. As a result, all events during the cardiac cycle can be viewed in a synoptic chart and aligned with the phases of the electrocardiogram.
In 1960 Denis Noble presented the first viable mathematical model of the cardiac action potential. These models adapted Hodgkin–Huxley equations to cardiac Purkinje fibres and demonstrated how ionic currents shape the plateau phase unique to cardiac tissue.
Regulation of the heartbeat
Ernst Heinrich Weber (1795-1878) and Wilhelm Eduard Weber (1804-1891) discovered in 1845 the inhibiting effect of the vagus nerve on the heart using the frog as an animal system, which was later used by Otto Loewi to discover the ‘Vagusstoff’. Like many German physiologists at the time, they were exploring the boundary between physics and physiology, studying the movement of fluids, which led to the hydrodynamic studies of blood flow. They analysed the resistance and elasticity of the vasculature to the blood flow. As a result, they proposed that blood flow was continuous once reaching capillaries. Albert v. Bezold (1826-1868), then at Jena, reported that of the cephalic end of the sectioned thoracic cord caused cardiac acceleration and a rise in mean blood pressure. He continued his experiments and, in 1867, demonstrated that the acceleration was primary and mediated by sympathetic fibers via the stellate ganglion. Oswald Schmiedeberg (1838-1921), under Ludwig’s guidance, in 1866, also discovered the accelerator nerve of the heart of the frog and of the dog, and in 1883, Leonard Charles Wooldridge (1857-1889) found centrifugal fibres to the heart of the dog, which alter the blood pressure without changing the rate of the beat. In the 1850’s Claude Bernard (1813–1878), made similar experiments in dogs showing how sympathetic and parasympathetic systems regulate heart rate and contractility.
In 1847, Carl Ludwig (1816-1895) invented the kymograph (or “wave-writer”), which revolutionized science by allowing researchers to record physiological events as they happened. He attached a stylus to a mercury manometer (blood pressure gauge). As the pressure pulsed, the stylus moved up and down on a revolving drum covered in smoked paper. For the first time, physicians had a permanent visual record of a heartbeat. Ludwig’s lab in Leipzig became a “factory of knowledge” where he and his students discovered the fundamental laws of the heart. Together with Henry Bowditch (1840-1911), he showed that a heart muscle cell either contracts fully or not at all; there is no “halfway” contraction. This is called the All-or-None law. In 1871 Bowditch also discovered the “Treppe” phenomenon, or staircase phenomenon, also called frequency-dependent activation. It refers to the idea that an increase in heart rate also increases the force of contraction generated by the myocardial cells with each heartbeat. He further proved that blood vessels are not just passive tubes but have “tone” controlled by the nervous system to maintain blood pressure. In 1856, he developed a method to perfuse a frog’s heart with a blood-like solution, keeping it beating for days. This allowed scientists to study the heart in isolation, for example in the experiments of Otto Loewi.
Adolf Eugen Fick (1829-1901) was the first to realize that you could calculate how much blood the heart pumps (cardiac output) without having to open the chest (1870). He applied the Law of Conservation of Mass to the lungs. The amount of oxygen a person breathes in must equal the amount of oxygen taken up by the blood as it passes through the lungs. By measuring the oxygen in the air that a patient breathes and comparing the oxygen levels in the arterial and venous blood, it can be calculated exactly how many liters of blood the heart is pumping per minute. This remains a vital technique in cardiology and intensive care.
Otto Frank (1865–1944) and Ernest Starling (1866–1927) demonstrated that the heart adjusts its force of contraction to venous return. They established the pressure–volume relationship fundamental to modern cardiology known as the Frank–Starling law. The Frank–Starling mechanism describes the heart’s intrinsic ability to increase stroke volume when more blood returns to it. As ventricular filling rises, cardiac muscle fibers stretch, and this stretch makes each heartbeat stronger—without needing extra neural or hormonal input.
As mentioned above the regulation of the heartbeat through the autonomous nervous system was established by the Weber brothers and Claude Bernard. This led to a new field in cardiac physiology resulting in the discovery of neurotransmitters by Otto Loewi (see the concept of neurotransmitters) and Henry Dale. In terms of heart research, the discovery of adrenergic receptors is most relevant. Walter B. Cannon (1871–1945), showed how emotional and environmental stress alter cardiac output, he integrated endocrine and autonomic influences on heart function. He expanded the homeostasis concept by placing the heart within a dynamic feedback system.
Walter Cannon and Arturo Rosenblueth formulated the “sympathin” hypothesis, proposing chemical mediators released by sympathetic nerves. They distinguished “sympathin E” (excitatory) and “sympathin I” (inhibitory). Although some of these ideas were misguided, further research by Ulf von Euler (1905-1983, Nobel Prize 1970) resulted in the identification of norepinephrine as the neurotransmitter of sympathetic nerves. However, the receptor side remained unclear until Raymond Ahlquist (1914-1983) published the landmark paper identifying α‑ and β‑adrenergic receptors in 1948. He demonstrated that β‑receptors mediate positive chronotropy (increased SA node firing) and positive inotropy (increased myocardial contractility). This was the first correct mechanistic explanation of how catecholamines act on the heart. This discovery directly enabled the development of β‑blockers by James Black (1924-2010 Nobel Prize 1988) in 1964.
The underlying cellular mechanism—how acetylcholine actually slows the heartbeat—was worked out decades after Loewi, primarily by electrophysiologists in the 1970s–1980s. David C. Brown and Terrence F. Brown demonstrated that acetylcholine directly activates a potassium current in cardiac pacemaker cells. This current hyperpolarizes the sinoatrial node and slows spontaneous depolarization. Their work also established the G‑protein–coupled mechanism that is now canonical.
This was the finally the mechanistic explanation of the regulation of the heartbeat: acetylcholine binds to M2 muscarinic receptors, activates G‑proteins, and opens GIRK (G‑protein–gated inward‑rectifier K⁺) channels, hyperpolarizing pacemaker cells, which are now more difficult to excite, thereby and slowing the heart.
The cultivation of individual cardiomyocytes was pioneered in the mid‑20th century by a small group of experimental physiologists and cell biologists—most notably Robert DeHaan, Paul F. Cranefield, and Brian F. Hoffman—who developed the first reliable methods for isolating and maintaining single beating heart cells in vitro. Their work created the foundation for modern cardiac electrophysiology, developmental biology, and stem‑cell–derived cardiomyocyte culture. Robert L. DeHaan (1930–2012) is widely credited with establishing the first robust methods for isolating and culturing single embryonic chick cardiomyocytes that continued to beat spontaneously in vitro beginning in the 1950s. His methods became the template for all later single‑cell cardiac culture systems. Paul F. Cranefield & Brian F. Hoffman (1950s–1970s), working at the Rockefeller Institute, refined the cultivation of individual cardiomyocytes for microelectrode recordings, enabling measurement of action potentials in single heart cells.
References
Silverman, M, Upshaw, C. Walter Gaskell and the understanding of atrioventricular conduction and block. JACC. 2002 May, 39 (10) 1574–1580.
Silverman, M. E., & Hollman, A. (2007). Discovery of the sinus node by Keith and Flack: On the centennial of their 1907 publication. Heart, 93(10), 1184. doi:https://doi.org/10.1136/hrt.2006.105049
Fye, W. Bruce. “Ernst, Wilhelm, and Eduard Weber.” Clinical Cardiology 23.9 (2009): 709.
Roguin A. Adolf Eugen Fick (1829-1901) – The Man Behind the Cardiac Output Equation. Am J Cardiol. 2020 Oct 15;133:162-165. doi: 10.1016/j.amjcard.2020.07.042. Epub 2020 Aug 16. PMID: 33172590.
