Divyan Bavan
Introduction
Blood holds many functions within organisms. To carry out these functions, it must be circulated in an efficient manner. This has been delegated to the heart. By conducting action potentials produced by pacemaker cells, cardiac muscle tissue is able to contract in a controlled manner, pumping blood throughout the body. While this explains the overall mechanism of the heart, a critical function of the heart is to adapt to physiological changes. For example, exercise causes muscle tissue to need more oxygen, and thus, more blood. This requires greater cardiac output. The regulatory mechanisms which control these adaptations can be split into two categories: intrinsic and extrinsic. While intrinsic mechanisms are embedded within the cardiac myocytes themselves, extrinsic control relies on neurotransmitters and hormones. Understanding these mechanisms and their roles in cardiac regulation is critical to understanding the cardiovascular system as a whole.
Intrinsic Regulation: The Frank-Starling Mechanism
As mentioned previously, exercise demands higher cardiac output. This increases venous return to the heart, and thus, venous pressure. The result of this is an increased volume of blood being pumped by the right ventricle to the pulmonary circuit. To compensate for this increase in volume, cardiac myocytes in the ventricles exhibit the Frank-Starling mechanism: a stretch-dependent increase in contractile force (Herring and Paterson, 2018).
Otto Frank first showed this mechanism in a frog heart. By making contractions isovolumetric, Frank demonstrated that increasing the diastolic fluid volume increased the pressure generated by the ventricle wall. Starling built upon this observation with a more quantitative study involving the isolated heart and lungs of a dog. He was able to show that as central venous pressure (CVP)—which was controlled by Starling through the height of a reservoir—increases, so does the ventricular output. Thus, Starling was able to quantitatively verify Frank’s observation (Herring and Paterson, 2018).
While the exact molecular mechanisms behind the Frank-Starling effect are still debated, there is consensus around the general process. When there is an increase in stroke volume, cardiac myocytes are stretched. This stretch induces two changes in the cells. The first is an increased sarcomere length. This causes less overlap between the thin actin filaments. In normal cardiac myocytes, the overlapping of these filaments causes myosin heads to act in the opposite direction of each other, decreasing efficiency. However, stretch—particularly to a length close to 2.2µm—leads to the filaments separating and increasing the efficiency of contraction. While this explains part of the mechanism, cardiac myocytes are far more sensitive to stretch than this model suggests. To explain this, a secondary mechanism has been proposed: calcium sensitization. Despite calcium concentrations staying constant, it appears that a higher fraction of cross-bridges are formed in stretched myocytes as opposed to unstretched myocytes. While there currently is not a concrete explanation for this phenomenon, titin and a fall in cross-sectional diameter may play roles in this effect (Herring and Paterson, 2018).
Aside from adjusting for venous return, the Frank-Starling mechanism is also heavily implicated in other functions. For example, gravity reduces the CVP as blood pools into the lower limbs when standing up. Therefore, when someone lies down, the CVP is increased. This leads to an increase in stroke volume, mediated by the Frank-Starling mechanism. Another critical responsibility of this mechanism is to ensure outputs of the right and left ventricle are equalized. This ensures that the pulmonary and systemic circuits do not get overfilled and congested (Herring and Paterson, 2018).
The Frank-Starling mechanism is often compromised in diseases such as heart failure. This can result from many factors, such as a reduction in contractility. The result of this is a flattened curve; stretch produces less force than would normally be expected. While this does pose a problem, it is often mitigated by an increase in CVP (Herring and Paterson, 2018). Therefore, the Frank-Starling mechanism is critical for the adaptation of the heart to various physiological changes.
Intrinsic Mechanisms: The Anrep Effect
While the Frank-Starling mechanism explains how the heart adapts to changes in CVP, it does not explain adaptations to changes in arterial pressure (AP). When there is an increase in AP, stroke volume is initially decreased. This leads to the accumulation of blood in the left ventricle, which eventually leads to increased contraction through the Frank-Starling mechanism. While this appears to solve the problem, it forces the heart to work at higher pressures and diastolic volumes (Herring and Paterson, 2018). This causes stress.
The Anrep effect is responsible for mitigating these effects. This effect works over longer time periods—about 5–10 minutes. At this point, several changes occur within the cardiac myocytes to strengthen contraction. The first is the activation of stretch-sensitive calcium channels; these act to boost the intracellular calcium concentration, increasing the recruitment of cross-bridges. This is reinforced by the activation of the Na+/H+ exchanger, which indirectly reduces the efflux of calcium from the myocytes. Finally, the myocardium produces inotropic agents such as myocardial angiotensin II and endothelin 1; these agents act in an autocrine manner to increase calcium influx. The result of this is an increase in contractile force without the increased volume and pressure (Herring and Paterson, 2018).
Extrinsic Mechanisms: Nervous Input
While the heart has the capacity to regulate itself, several other factors influence its behaviour as well. The first mechanism of extrinsic control is nervous input. The heart is controlled by the autonomic nervous system, which has two components: the sympathetic and parasympathetic divisions. These divisions have opposing effects on the heart, and control its output dependent on the physiological state of the organism.
The parasympathetic division controls the body during the resting state. This means that cardiac output can be slowed down. To achieve this, the parasympathetic nervous system relies on the vagus nerve to extend its influence on the heart. This nerve is the 10th cranial nerve from the brain, and synapses near the heart with postganglionic parasympathetic neurons close to the heart. The postganglionic neurons then synapse onto the heart, releasing acetylcholine. This causes decreases in both chronotropy and dromotropy. In the SA node, acetylcholine binds to M2 receptors—GPCRs associated with a Gi subunit. The activation of this receptor reduces the output of cAMP by adenylyl cyclase. This leads to less HCN channels being activated, directly reducing the rate of firing. The reduction of cAMP also leads to less activation of L-type calcium channels by protein kinase A, slowing down depolarization. Finally, the βγ subunit of the receptor activates GIRK channels: potassium channels which increase repolarization. These effects together lead to a reduction in heart rate. While the AV node does not express HCN channels heavily, it is affected by the other two changes, reducing dromotropy. Surprisingly, the parasympathetic division does not have much effect on inotropy (Klabunde, 2021; Koeppen and Stanton, 2017).
The sympathetic nervous system takes these effects and essentially reverses them. This is because this division is responsible for increasing cardiac output in response to danger, among other scenarios. The sympathetic nervous system arises from preganglionic neurons in the spinal cord, which synapse onto the sympathetic chain (Alshak et al., 2023). The postganglionic neurons regulating cardiac output then travel to the heart, where they release noradrenaline. This binds to β1 adrenergic receptors: GPCRs associated with the Gs subunit. This leads to elevated cAMP and protein kinase A (PKA) activation. Aside from chronotropy and dromotropy, which are reversed with respect to the parasympathetic division, sympathetic stimulation also increases inotropy and lusitropy. PKA phosphorylates L-type calcium channels in ventricular myocytes, increasing the force of contraction. PKA also phosphorylates phospholamban and troponin I, which increase the reuptake of calcium and reduce the sensitivity of contractile proteins to calcium, respectively. Thus, it is evident that neural input from the autonomic nervous system is critical for regulating cardiac output (Klabunde, 2021; Koeppen and Stanton, 2017).
Extrinsic Mechanisms: Chemical Control
Like acetylcholine and noradrenaline, several chemicals can influence cardiac output. For example, adrenaline from the adrenal medulla causes similar effects to the sympathetic nervous system. The adrenal cortex also releases a hormone called hydrocortisone, which amplifies the effects of catecholamines. Other hormones such as thyroid hormones, insulin, glucagon, and thyroxine also play important roles in cardiac regulation (Koeppen and Stanton, 2017).
Conclusion
By looking at the diverse mechanisms behind the control of cardiac output, it is evident that each has a distinct role in adapting to physiological changes. For example, the Frank-Starling mechanism is important for rapid changes in contractile force. This is critical for ensuring cardiac output remains tied to central venous pressure. However, when arterial pressure increases, this mechanism can’t compensate fully. This is where the Anrep effect comes into play, increasing inotropy to ensure greater contraction without chronically elevated diastolic pressure. However, when cardiac output needs to be coupled with overall shifts in the body, extrinsic mechanisms become essential. The autonomic nervous system regulates changes through distinct molecular pathways, influencing the many characteristics of cardiac function. Hormones act in unison, exerting their influence on the myocardium as well. By understanding these regulatory mechanisms, it becomes possible to extend our own influence in cases of disease. Therefore, continuing to develop our understanding of these pathways is essential for advancing cardiovascular medicine.
Works Cited
Alshak, Mark N, and Joe M Das. “Neuroanatomy, Sympathetic Nervous System.” Nih.gov, StatPearls Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK542195/.
Herring, Neil, et al. Levick’s Introduction to Cardiovascular Physiology. 6th ed., Boca Raton, CRC Press, 2018.
Klabunde, Richard E. Cardiovascular Physiology Concepts. 3rd ed., New York, Wolters Kluwer Medical, 2021.
Koeppen, Bruce M, and Bruce A Stanton. Berne and Levy Physiology. 7th ed., Saintt Louis Elsevier Health Sciences, 2017.