Brief Review of the Cardiac Action Potential

The Cardiac Action Potential. The main currents responsible for the action potential are the rapid influx of sodium during depolarization and the outward flow of potassium through two delayed rectifying currents (Rapid/IKr and Slow/IKs) during repolarization

 

The Cardiac Action Potential occurs in Five (5) Phases:

Phase 0 represents rapid ventricular depolarization which is primary due to the rapid increase in sodium conductance (gNa+) accompanied by a fall in potassium conductance (gK+)

Phase 1 represents the very initial stages of repolarization caused by inactivation of sodium currents and simultaneous opening of special potassium channels

Phase 2 is the isoelectric plateau phase and is primarily due to an increase in slow inward calcium conductance (gCa++) through L-type Calcium channels and outward potassium currents

Phase 3 is the rapid repolarization phase resulting from an increase in potassium conductance and a decrease in calcium conductance (i.e., calcium channels close while potassium channels remain open).

Phase 4 is a true resting potential that primarily reflects a high potassium conductance

ERP, Effective Refractory Period 

Channels and ions involved in the cardiac action potential:

What is the QT interval?

The QT interval is found on standard electrocardiograms (ECG or EKG) and represents the interval measured from the onset of ventricular  depolarization (onset of QRS complex) to the end of ventricular repolarization (end of the T wave). It is important to note that ventricular depolarization AND repolarization are occurring simultaneously during the QT interval. See the figure below. 

A normal QTc interval is generally defined as <460 ms for women and <450 ms for men

Why do we care about the QT interval?

Prolongation of the QT interval is an important risk factor for the development of a potentially fatal polymorphic ventricular tachycardia known as Torsades de Pointes (TdP)–translated as “Twisting of Points/Peaks”. TdP is a malignant ventricular arrhythmia.

Potential causes of QT prolongation include, but are not limited to Electrolyte abnormalities, gene mutations, and medications.

Many psychotropic medications are known to prolong the QT interval to varying degrees which significantly increases the risk of developing TdP. 

 

Fun Fact: QT prolongation remains a common reason the FDA rejects new medications. 

What is the Corrected QT Interval (QTc) and why do we use it?

The QT interval varies with heart rate, age, and sex of the individual. At faster heart rates, the QT interval shortens. The purpose of the QTc is to adjust for heart rate (HR), since increased HR underestimates the QT Interval and can be misleading. In addition, most studies use the QTc to stratify risk, which is the purpose of measuring QT interval to begin with.

How is the Corrected QT Interval (QTc) Calculated?

Although many EKG machines are pre-programmed to calculate the QTc, it might be helpful to know how it does this.

Two formulas can be used to calculate QTc from standard EKG readings:

  1. Bazett’s formula: QTc = QT/√RR
  2. Hodges formula: QTc = QT + 1.75[HR-60]

**Note that these formulas do not accurately calculate QT at extremely slow heart rates or extremely fast heart rates.** 

Is there a quick way to identify QT prolongation without doing math?

Yes. If the QT interval appears to be greater than half of the RR interval than any provider can easily identify QTc prolongation (but this only works if heart rate is close to 60 bpm)

How do medications prolong the QT interval?

Recall that repolarization of the ventricle primarily occurs due to the outward flow of potassium via two potassium rectifying currents (IKr and IKs). Blockade of either current may prolong the action potential and thereby lengthen the QT interval.

When is the best time to check for medication-induced QTc Prolongation?

The most accurate assessment of pharmacologic QT prolongation using ECG occurs at or near the maximum daily blood level of medications affecting the QT interval.

What is the relationship between QT prolongation and cardiovascular risk?

The relationship between QTc prolongation and cardiac mortality/sudden death is very complex but appears to be a graded relationship. 

“QTc interval prolongation has a graded relationship to the risk of cardiac mortality and sudden death (presumably related to TdP in many cases), although the risk of sudden death, at the individual level, remains low. It has been suggested that the hazard ratio for cardiac events linked to the QTc is 1.052X  where “x” is 1 ms increase in QTc over 400 ms. Thus, a patient with a QTc of 500 ms would have a 1.66-fold greater risk of such a cardiac event than a patient with a QTc of 400 ms, whereas a patient with a QTc of 550 ms would have a 2.14-fold greater risk.” (Beach et al 2013, Psychosomatics)

The Hazard Ratio (HR) can be thought of as the "fold" increased risk of a potentially lethal cardiac arrhythmia compared to an individual with QTc of 400ms. Therefore an individual with a QTc of 500ms has a 1.66 fold increased risk of fatal arrhythmia compared to an individual with QTc of 400ms.

Risk Factors For Adverse Events

  • Female
  • Increased Age
  • Congenital LQTS
  • Electrolyte Abnormalities
    • Hypokalemia
    • Hypocalcemia
    • Hypomagnesemia
    • Hypoglycemia
  • Anorexia Nervosa
  • Diuretic Use
  • Bradycardia
  • Left Ventricular Dysfunction
  • Heart Failure
  • Mitral Valve Prolapse
  • Myocardial Infarction
  • Renal Disease
  • Hepatic Disease
  • Hypertension (via diastolic dysfunction)
  • Diabetes (via electrolyte disturbances)
  • Hypothyroidism (via electrolyte disturbances)
  • AIDS
  • Pituitary Insufficiency (via electrolyte disturbances)
  • Malnutrition (via electrolyte disturbances)
  • Obesity (via electrolyte disturbances)
  • Central Nervous System (CNS) Injury – Stroke, Trauma, Tumor, Infection (via electrolyte disturbances)

Psychiatric Medications and QTc Prolongation

  • J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  • Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  • Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  • Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
  • Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
  • Beach, SR et al. QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update. Psychosomatics. 2018 Mar – Apr;59(2):105-122. doi: 10.1016/j.psym.2017.10.009. Epub 2017.

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