Myocardial contractility

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Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction. [ citation needed ]

Contents

Mechanisms for altering contractility

Increasing contractility is done primarily through increasing the influx of calcium or maintaining higher calcium levels in the cytosol of cardiac myocytes during an action potential. This is done by a number of mechanisms:[ citation needed ]

  1. Sympathetic activation. Increased circulating levels of catecholamines (which can bind to β-Adrenergic activation) as well as stimulation by sympathetic nerves (which can release norepinepherine that binds to β1-adrenoceptors on myocytes) causes the Gs subunit of the receptor to render adenylate cyclase activated, resulting in increase of cAMP - which has a number of effects including phosphorylating phospholamban (via Protein kinase A).
  2. Phosphorylating phospholamban. When phospholamban is not phosphorylated, it inhibits the calcium pumps that pump calcium back into the sarcoplasmic reticulum. When it's phosphorylated by PKA, levels of calcium stored in the sarcoplasmic reticulum are increased, allowing a higher rate of calcium being released at the next contraction. However, the increased rate of calcium sequestration also leads to an increase in lusitropy.
  3. Sensitizing troponin-C to the effects of calcium.
  4. Phosphorylating L-type calcium channels. This will increase their permeability to calcium, allowing more calcium into the myocyte cells, increasing contractility.
  5. An abrupt increase in afterload enhances myocardial contractility and prolongs systolic ejection time through the Anrep effect. This response involves a two-phase recruitment of myosin from resting states to contraction-ready configurations, boosting the heart's contractile force. [1] [2]
  6. An increase in heart rate also stimulates inotropy (Bowditch effect; treppe; frequency-dependent inotropy). This is probably due to the inability of Na+/K+-ATPase to keep up with the sodium influx at the higher frequency of action potentials at elevated heart rates [3]
  7. Drugs. Drugs like digitalis can act as a positive inotropic agent by inhibiting the Na+/K+ pump. High Na+ concentration gradient is necessary to pump out sarcoplasmic calcium via the Na+/Ca++ antiporter. Inhibition of the Na+/K+ causes extra sodium to accumulate inside the cell. The buildup the Na+ concentration inside the cell will cause the gradient from inside the cell to the outside of the cell to decrease slightly. This action will make it more difficult for calcium to leave the cell via the Na+/Ca++ antiporter.
  8. Increase the amount of calcium in the sarcoplasm. More calcium available for Troponin to use will increase the force developed.

Decreasing contractility is done primarily by decreasing the influx of calcium or maintaining lower calcium levels in the cytosol of cardiac myocytes during an action potential. This is done by a number of mechanisms:[ citation needed ]

  1. Parasympathetic activation.
  2. If the heart is experiencing anoxia, hypercapnia (increased CO2) or acidosis, the heart cells will enter a state of dysfunction and not work properly. Correct sarcomere crossbridges will not form the heart becomes less efficient (leading to myocardial failure).
  3. Loss of parts of the myocardium. Heart attack can cause a section of the ventricular wall dies off, that portion cannot contract and there is less force developed during systole.

Inotropy

A measurable relative increase in contractility is a property of the myocardium similar to the term "inotropy". Contractility may be iatrogenically altered by the administration of inotropic agents. Drugs that positively render the effects of catecholamines such as norepinephrine and epinephrine that enhance contractility are considered to have a positive inotropic effect. The ancient herbal remedy digitalis appears to have both inotropic and chronotropic properties that have been recorded encyclopedically for centuries and it remains advantageous today.[ citation needed ]

Model as a contributing factor

Under one existing model [ citation needed ], the five factors of myocardial performance are considered to be

By this model, if myocardial performance changes while preload, afterload, heart rate, and conduction velocity are all held constant, then the change in performance must be due to a change in contractility. However, changes in contractility alone generally do not occur. [ citation needed ] Other examples:

Related Research Articles

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<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

SERCA, or sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

<span class="mw-page-title-main">Muscle contraction</span> Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

<span class="mw-page-title-main">Phospholamban</span> Mammalian protein found in Homo sapiens

Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.

<span class="mw-page-title-main">Milrinone</span> Chemical compound

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.

<span class="mw-page-title-main">Levosimendan</span> Pharmaceutical drug

Levosimendan (INN) is a calcium sensitizer used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax. Overall the drug has a two fold mechanism of action. It leads to greater inotropy by increasing the calcium sensitivity as it binds to troponin and this results in a greater positive inotrophic force. Secondly, the drug is able to open ATP sensitive potassium channels in vascular smooth muscle cells, and the vascular dilatory effects of the drug lead to a decreased preload and afterload, putting less work on the heart. This drug is in the process of review by the FDA but has not been approved for use in the United States yet.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

<span class="mw-page-title-main">Autoregulation</span> Adjustment within a biological system

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Within the muscle tissue of animals and humans, contraction and relaxation of the muscle cells (myocytes) is a highly regulated and rhythmic process. In cardiomyocytes, or cardiac muscle cells, muscular contraction takes place due to movement at a structure referred to as the diad, sometimes spelled "dyad." The dyad is the connection of transverse- tubules (t-tubules) and the junctional sarcoplasmic reticulum (jSR). Like skeletal muscle contractions, Calcium (Ca2+) ions are required for polarization and depolarization through a voltage-gated calcium channel. The rapid influx of calcium into the cell signals for the cells to contract. When the calcium intake travels through an entire muscle, it will trigger a united muscular contraction. This process is known as excitation-contraction coupling. This contraction pushes blood inside the heart and from the heart to other regions of the body.

The Bowditch effect, also known as the Treppe phenomenon or Treppe effect or Staircase Phenomenon, is an autoregulation method by which myocardial tension increases with an increase in heart rate. It was first observed by Henry Pickering Bowditch in 1871.

The Anrep effect describes the rapid increase in myocardial contractility in response to the sudden rise in afterload, the pressure the heart must work against to eject blood. This adaptive mechanism allows the heart to sustain stroke volume and cardiac output despite increased resistance. It operates through homeometric autoregulation, meaning that contractility adjustments occur independently of preload or heart rate.

Lusitropy or lucitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility, but the myocardial relaxation, or lusitropy, decreases. This should not be confused, however, with catecholamine-induced calcium uptake into the sarcoplasmic reticulum, which increases lusitropy.

Bathmotropic often refers to modifying the degree of excitability specifically of the heart; in general, it refers to modification of the degree of excitability of musculature in general, including the heart. It especially is used to describe the effects of the cardiac nerves on cardiac excitability. Positive bathmotropic effects increase the response of muscle to stimulation, whereas negative bathmotropic effects decrease the response of muscle to stimulation. In a whole, it is the heart's reaction to catecholamines. Conditions that decrease bathmotropy cause the heart to be less responsive to catecholaminergic drugs. A substance that has a bathmotropic effect is known as a bathmotrope.

Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.

A plot of a system's pressure versus volume has long been used to measure the work done by the system and its efficiency. This analysis can be applied to heat engines and pumps, including the heart. A considerable amount of information on cardiac performance can be determined from the pressure vs. volume plot. A number of methods have been determined for measuring PV-loop values experimentally.

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Mydicar is a genetically targeted enzyme replacement therapy being studied for use in patients with severe heart failure. It is designed to increase the level of SERCA2a, a sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an adeno-associated viral vector. Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle. Mydicar is being tested in a phase 2 study, in which has been compared to a placebo in 39 advanced heart failure patients. Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo.

<span class="mw-page-title-main">Istaroxime</span> Chemical compound

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

References

  1. ↑ Reil, Jan‐Christian; Reil, Gert‐Hinrich; Kovács, Árpád; Sequeira, Vasco; Waddingham, Mark T.; Lodi, Maria; Herwig, Melissa; Ghaderi, Shahrooz; Kreusser, Michael M.; Papp, Zoltán; Voigt, Niels; Dobrev, Dobromir; Meyhöfer, Svenja; Langer, Harald F.; Maier, Lars S. (August 2020). "CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect". The Journal of Physiology. 598 (15): 3129–3153. doi:10.1113/JP279607. ISSN   0022-3751. PMC   7657994 . PMID   32394454.
  2. ↑ Sequeira, Vasco; Maack, Christoph; Reil, Gert-Hinrich; Reil, Jan-Christian (2024-01-05). "Exploring the Connection Between Relaxed Myosin States and the Anrep Effect". Circulation Research. 134 (1): 117–134. doi:10.1161/CIRCRESAHA.123.323173. ISSN   0009-7330.
  3. ↑ Richard Klabunde (3 November 2011). Cardiovascular Physiology Concepts. Lippincott Williams & Wilkins. ISBN   978-1451113846.
  4. 1 2 Klabunde, Richard. "Cardiac Inotropy (Contractility)". Cardiovascular Physiology Concepts. Retrieved 27 January 2011.
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