Dyspnea is common. We all experience it when we exercise or, if we have medical problems like asthma, when we’re acutely ill. And dyspnea is a common symptom reported by hospitalized patients. As a medical student, I learned early on to ask about chest pain. I also learned that, if the answer was “yes”, I should follow this up with “any shortness of breath or sweating”? Although there are myriad reasons other than acute coronary syndromes why chest pain and dyspnea might both be present (e.g., pulmonary embolism), the concern for acute myocardial infarction was what prompted this question cascade.
But why does myocardial ischemia lead to dyspnea? That question informed a tweetorial way back in June 2018 and was also the topic of episode 8.
Emergence as anginal equivalent
The connection between coronary ischemia and dyspnea has been made for centuries. William Heberden (1768) and William Osler (1910) both noted the connection. But the idea of an anginal equivalent didn’t emerge until later.
Some data from 1968 was provocative. Phibbs, Holmes, and Lowe studied 184 patients with coronary artery disease without known heart failure or cardiomegaly. Each patient underwent stress testing. When they were noted to have ischemic change on ECG, they were asked about symptoms. Here’s what they found
- 27% reported dyspnea alone
- 24% reported dyspnea followed by pain
- 17% reported angina alone
- 11% reported no symptoms
The investigators were able to reproduce these results on repeat stress testing. They cautioned that “history taking limited to pain or painful discomfort does not seem adequate in the search for symptoms of transient stress-induced myocardial ischemia.”
Again, these patients were not known to have heart failure, so “blaming” the dyspnea on this syndrome does not seem adequate.
Interrogate the left ventricle
While the explanation involves both the heart and the lungs, it begins with the heart. An early clue was identified in the mid-1900s when catheters were first used to measure pressures in the ventricle.
Early observations showed that during ischemia, there is a rise in left ventricular end-diastolic pressure (LVEDP). For example, in 1968 Ben McAllister and a group at Mayo Clinic published a report on the change in LVEDP during exercise. They examined 19 patients with coronary artery disease and angina and 5 who had no coronary artery disease. The patients with coronary artery disease had higher resting LVEDP (19 mmHg versus 16 mmHg). LVEDP also increased more with exercise: 19 to 30 mmHg versus 16 to 20 mmHg. The other thing they found was a blunted increase in LVEDP after pretreatment with nitroglycerin.
A question emerged: why does LVEDP increase and why might this lead to the sensation of dyspnea?
Increased volume or Decreased Compliance?
At least two things determine LVEDP: left ventricular end-diastolic volume (LVEDV) and left ventricular compliance. If more volume enters a heart with unchanged compliance, the pressure increases. Alternatively, if the same volume enters and the compliance has decreased, the pressure will also increase.
One study, published in 1972 by Carl Pepine and Leslie Weiner, suggested decreased compliance was the factor leading to increased LVEDP in ischemia. They used atrial pacing to induce ischemia while measuring both LVEDP and LVEDV. As the LVEDP increased the volume did not. Instead, they found a decrease in compliance. With ischemia the left ventricle is stiffer due to decreased compliance. These findings have been confirmed in subsequent studies.
Why does compliance decrease? While there have been several competing theories, the rigor bond theory has prevailed.
It is important to remember that myocardial relaxation is an energy-dependent process. More specifically, ATP is required. It is used to pump free cytoplasmic calcium back into the sarcoplasmic reticulum and to dissociate the actino-myosin cross-bridge. In the setting of decreased coronary perfusion, the myocardial has less oxygen for ATP creation. ATP levels drop and the ATP-dependent myocardial relaxation is blunted. The result is decreased left ventricular compliance and increased LVEDP.
What about dyspnea?
Despite the hemodynamic changes mentioned thus far, none of them explain dyspnea. We have to add a few pieces to the puzzle. First, recall that the increased LVEDP is transmitted to the left atrium and to the pulmonary vasculature. There are at least two ways that this might lead to the sensation of dyspnea
- Decreased lung compliance
- Interstitial edema that activated c-fibers
One of the studies noted earlier (Pepine, 1972) found that lung compliance decreases as a result of the increase in LVEDP. The hypothesis is that interstitial edema, which results from increased pulmonary pressures, leads to worsening lung mechanics.
The other major hypothesis is that c-fibers (also known as Juxtacapillary or J-receptors) are activated with pulmonary vascular congestion and lead to the sensation of dyspnea via vagal stimulation. A number of case reports have shown that vagotomy can alleviate the sensation of dyspnea. For example, one report discussed a 43-year-old patient with unilateral pulmonary venous obstruction and intractable dyspnea. She eventually underwent unilateral vagus nerve interruption with complete resolution of her symptoms.
While there is confidence regarding the early mechanism of ischemia-induced dyspnea (i.e., decreased LV compliance and increased LVEDP), the relative contribution of worsening lung mechanics and activation of c-fibers (or some other ill-defined mechanism) is less clear.
Here’s a flow diagram putting it all together.
Is there clinical relevance?
While this mechanism is interesting and provides support for the idea of asking about dyspnea when we’re concerned about an acute coronary syndrome, it’s worth wondering about other applications and clinical correlates. There are a few.
If left ventricular ischemia and decreased compliance lead to dyspnea, it might follow that only left ventricular ischemia would cause dyspnea and that more severe ischemia might lead to more dyspnea. One study supported this hypothesis as it found that anterior infarctions were more often presented by dyspnea. Interestingly, they were also more associated with cough, something that is also provoked by stimulation of c-fibers.
Dyspnea is also associated with worse outcomes. One study found increased mortality in those with “non-painful” myocardial infarctions.
One other cool connection: The dyspnea seen with ticagrelor may be related to this mechanism. Ticagrelor inhibits clearance of adenosine and adenosine activates c-fibers by the A1 receptor!
Take home points
- Myocardial ischemia leads to decreased LV compliance and increased LVEDP
- Increased LVEDP is transmitted to the LA and to the pulmonary venous system
- This leads to interstitial congestion
- Interstitial congestion leads to dyspnea, likely from either decreased lung compliance or activation of pulmonary c-fibers.
- Understand importance of elevated left ventricular end-diastolic pressure in the pathophysiology of ischemia-induced dyspnea.
- Outline competing theories for how an increase in left ventricular end-diastolic pressure leads to dyspnea.
- Appreciate the clinical relevance of dyspnea as a presenting symptoms of acute coronary syndrome.
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Listen to the episode
Credits & Citation
◾️Episode written by Tony Breu
◾️Episode audio edited by Clair Morgan of Nodderly
◾️Show notes by Tony Breu
Breu AC, Cooper AZ, Abrams HR. Why is dyspnea an anginal equivalent? The Curious Clinicians Podcast. September 3, 2020. https://curiousclinicians.com/2020/08/28/episode-8-why-is-dyspnea-an-anginal-equivalent/(opens in a new tab)
Opening image source: https://cvphysiology.com/Cardiac%20Function/CF014