Talking Tall Rounds®: Utility of Metabolic Exercise Testing in Cardiovascular Disease

Podcast Transcript

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Emanuel Finet, MD:

I'm going to start quickly by having an overview of what it is, a metabolic exercise stress test, and how we get to the information that we normally get. If we truly want to know how a car runs, you've got to take it for a test drive. In a similar way, you have to exercise the heart to actually understand the full potential and circulatory performance of the heart. Not only does the flow rate increase by about 300 to 400% with exercise, but actually the distribution changes quite a bit from 11% of perfusion with the skeletal muscle at rest to about 87 to 90% during peak exercise for the purpose of respiration.

Respiration is the molecular metabolism of oxygen. Obviously, it's regulated by multiple layers in the central nervous system, in which we generate movement of diaphragms and regulation overall of all these processes. The uptake of oxygen by the lungs, the delivery by the circulatory system, and ultimately the obstruction of oxygen by the skeletal muscle.

During exercise, the majority of the blood pool is actually in the skeletal muscle, for the purpose of respiration. We can actually study the metabolic sufficiency of the circulatory system by the study of respiration. I am not going to bog down too much on this, but this is pretty much how mitochondrial respiration works. There are four phases: glycolysis, the synthesis of acetyl-CoA, the Krebs cycle, and ultimately electron response change.

What I want you to focus on mainly is that, for the purpose of respiration, by the metabolism of glycogen into eventually glucose and pyruvate, there's lactate that gets bypassed and it eventually gets metabolized into glucose by the Cori cycle during some time, but it reaches a maximal point in which the lactate continues to increase with exercise.

Metabolism of pyruvate into acetyl-CoA produces CO2, which is eliminated in the veins, in the venous blood, and eventually exhaled during respiration. Then, after acetyl-CoA enters into the Krebs cycle, it helps in the phosphorylation of ADP (adenosine diphosphate) into ATP (adenosine triphosphate), which produces energy in the muscle, and that leads to the consumption of oxygen.

So, during respiration, we consume oxygen, we eliminate CO2 and we produce lactate as a byproduct. Therefore, when you plot oxygen uptake by humans proportional to the workload, you can see how there's a pretty significant, directly proportional increase until the maximal workload. At the same time, you see this increase in lactate that, at the beginning, is sort of flattened because it's being buffered, but eventually increases exponentially. This exponential point in which the lactate shifts to more than what it had before, we call that anaerobic threshold, and we can measure that during ventilation.

At the same time, we see a proportional increase in the heart rate, about 120 to 170%, and also in the stroke volume with exercise that is proportional to the work rate of the oxygen uptake, finally to give us an increased cardiac output of about 300 to 100% increase with exercise.

So, you can see then that the cardiac output and the oxygen uptake are directly correlated proportionally to a change in cardiac output over a change in VO2 that has a ratio of five, approximately. At the same time, you also see an increase in the oxygen extraction at the mitochondrial level. We measure that by the difference in arterial to venous oxygen content. You can see how, over time, the oxygen content drops in the mixed venous blood that is measured normally in the pulmonary artery, whereas in the artery remains the same.

You can see this on the cycle and the treadmill. This is a CPET (cardiopulmonary exercise testing). It has different components in which we measure the airflow. We measure three things, mainly flow, the proportion of CO2 and the proportion of oxygen, which we plot those over time, and we have different curves. When we combine those curves. Eventually we create this panel, which we call a Wasserman 9-Panel panel chart, which is the minute ventilation, the volume of CO2 and volume of O2, time, heart rate, blood pressure work. When we measure ABGs, we have lactate and pHs as well.

So, this is a report that we currently have that has three components: the exercise, cardiovascular stress data, metabolic and ventilatory data. We also have additional prognostic data that we have at the very bottom. You can actually go to the image part of the test and actually see the metabolic data that we record as well as all the ECGs.

We have something like this. Just to orient to, for example, in plot two, we have changes in heart rate and oxygen pulse, which is a surrogate of stroke volume. As you see, VO2 is a surrogate of cardiac output, therefore a VO2 divided by heart rate is a surrogate of the stroke volume. You can see how they change over time. The peak VO2 is a surrogate of the cardiac output, so you can see how it increases over time. Then we can see other parameters of aerobic efficiency, RV function, PA pressure, and so on.

There's a glossary that we have on the summary on the report. Each of these parameters that we measure actually has a particular name. For example, peak VO2, we call it aerobic capacity, or peak RER, which is the relationship between VCO2 and VO2, called aerobic effort. All of them have a particular meaning and most of them actually are predictors.

So, in Cleveland Clinic, not too long ago, Dr. Wael Jaber and some of our fellows published how important peak VO2 is in the predictability of more mortality in over 120,000 patients. But this predictor VO2 and also other predictors that we measure have all been associated with cardiovascular outcomes, very strongly, even at the same ejection fraction. which we're going to hear next.

Sanjeeb Bhattacharya, MD:

We're going to talk about the utilization of cardiopulmonary exercise testing or metabolic stress testing in pulmonary hypertension patients. It's only five minutes, so I only have two objectives. We're going to talk about the historical evaluation of PH patients. Then we're going to talk about how to incorporate CPET in the diagnosis, management and prognostication of these patients who are super sick.

There's five groups of pulmonary hypertension. This is five minutes. I don't have time to go through everything. We're going to talk about group one, which is the one I think everybody gets worried about the most when we see them in clinic. These are the patients who have idiopathic, heritable pulmonary hypertension, pulmonary hypertension related to connective tissue disease and adult congenital heart disease patients. Again, not a very common thing we see in clinic. It's one of the more rare things, but very important that we don't miss it when we see it and we know how to manage them appropriately.

So, risk assessment for WHO group 1, pulmonary hypertension, typically will consist of a six-minute walk test. These are submaximal studies. Hemodynamics, which are the gold standard of diagnosing pulmonary hypertension, where we're looking at RA pressure, mean PA, cardiac indices, and PVR, pulmonary vascular resistance. Understanding the demographics of the patients, knowing that some demographics have higher risks than others. Then cardiac biomarkers, whether it's NT-proBNP or BNP.

These are the typical risk calculators that we use when we see these patients in clinic on index. As we follow them, on and how they're doing on medical therapy. There's the REVEAL risk score, which looked at the REVEAL registry, looking at certain risk factors that they thought were more important, looking at things like a subgroup of group one, male age greater than 60 being an adverse risk factor, eGFR, WHO or NYHA class, blood pressure, heart rate, all-cause hospitalization, six-minute walk test, et cetera.

Then the COMPERA registry, which was a different registry, looked at their own data and they came up with a more simplified version, looking at three parameters: functional class, six-minute walk test distance and NT-proBNP. They're able to risk stratify these patients. It’s very helpful when we see these patients in clinic on index and as we treat them going forward.

But can we gain any insight from really maximal exercise testing? And I think the one thing we can say is yes. Then the second thing we can say is that, historically, we think maybe these patients are too high risk for exercise studies. We worry about syncope, things like that. It's been shown over and over again that this is a safe study modality to do in pulmonary hypertension patients.

So, what's happening during exercise physiology? We see in pulmonary hypertension, we have an increased pulmonary vascular resistance, a decrease in the pulmonary capillary bed for oxygen exchange. We have two pathways where you have VQ mismatching, kind of this effective right to left shunting due to that destruction of the capillary bed, or actual intracardiac shunts that may pop up during exercise, leading to an increase in dead space for the decrease in tidal volume, a decrease in partial oxygen and pH and increase in ventilatory requirements. This is that physical dyspnea that patients will feel.

More hemodynamically where you have this increase in PVR, you have this uncoupling of the RV and PA leading to increased lactate, decrease in ATP generation, impaired muscle contraction, muscle fatigue. How do we kind of see this on CPET? Well, if you see on the right here, it leads to things that are surrogates for decrease in cardiac output all the way on the right. This is a decrease in the VO2 work relationship, decrease in our stroke volume surrogate, which is O2 pulse, decrease in the anaerobic threshold. If we're measuring lactate, we see a big spike in lactate very early, a decrease in pH and a decrease in the carbon dioxide being exhaled.

We can also see the increase in minute ventilation, which is your VE, the increase in dead space, which is your Ve/VCO2 surrogate, which is a marker. Again, end-tidal CO2 will plummet, not only at the beginning of exercise, but as you start exercising further and further. This leads to that exercise intolerance, leg fatigue and shortness of breath.

So diagnostically, can we diagnose PA from cardiopulmonary exercise tests? The answer is no, but we can gain some clues if we're seeing a patient in clinic, sending them for an exercise test, and we can say, "This is dyspnea NOS, but what could be driving it?" So gold standard is, still, everybody needs a right heart cath to really confirm and phenotype pulmonary hypertension.

But what we can say is if we're seeing patients with this dyspnea NOS going for cardiopulmonary exercise testing or metabolic testing, we can see a decrease in VO2, a decrease in the work rate, O2 pulse, a decrease in the PET CO2 at rest and at anaerobic threshold, and then we'll see an increase in that dead space, which is that dead space over tidal volume and also the Ve/VCO2 . These are clues. It doesn't diagnose it, but it gives you a clue that, "Hey, there might be something in the pulmonary vascular bed that we have to look out for." Now it doesn't tell you group 1 versus group 5 versus group 2, but it sends up a spidey signal that, "Hey, we need to maybe look at this in a little more detail."

What I use it a little bit more for is more prognostication and really managing these patients with intervention, especially these patients where you're trying to get them into a low-risk group phenotype.

So prognostically, peak VO2 has been shown to have a 1.5 times mortality risk if your peak VO2 is less than 10.4 Ve/VCO2 greater than 60 and oxygen desaturation on top of your six-minute walk test gives you added prognostic information where the mortality can increase five or seven fold over just doing a six-minute walk test.

Then monitoring on intervention where you see low risk profiles where their peak VO2 gets above 15 or greater than 65% predicted peak VO2. The Ve/VCO2 slope then decreases less than 35. You see that on intervention, these are more of a low-risk profile patient.

In small studies, and again, a lot of these are just small single-center studies, we see that maybe improvements in peak VO2, improving peak heart rate and O2 pulse, which is that surrogate for stroke volume, might correlate with improvements in RV function and could have improved predictors of survival.

So the key takeaway is that historically, risk stratification upon diagnosis rarely includes CPET in the management of pulmonary hypertension, but I think it does hold valuable insights, not only to lead you to a possible diagnosis, but also prognostic information and how well your patient is doing longitudinally on therapy. Thank you.

Tamanna Singh, MD:

Good morning, everybody. Okay, we're going to take a little bit of a shift and talk about some really active people.

So in my practice, exercise testing, specifically cardiopulmonary exercise testing, is really the cornerstone of how we not only diagnose, but manage and provide exercise guidelines for individuals who are symptomatic coming in with cardiovascular abnormalities, and certainly in individuals who are looking more specifically for some sort of risk assessment.

This is what we use in terms of our pre-participation assessment of athletes. Typically, when we see any sort of signal, whether it be in their history, the familial history, or by initial imaging, whether it be EKG and echo, if we're looking to do functional testing, we'll immediately go towards cardiopulmonary exercise testing.

As you've already heard through many of the talks this morning, it's incredibly useful in terms of all of the data that it provides from a cardiac pulmonary neuromuscular perspective. I do want to highlight what Dr. Saka had mentioned in his presentation that we really do favor RAMP protocols for all of our athletes. In general, I would encourage that for anyone who is exercising just because it's actually going to be closer to the true VO2 for that individual than a more stepwise approach with a Bruce protocol.

So, when you are ordering your stress test and seeking cardiopulmonary exercise testing, and you have someone who is very active, we do have athlete protocols that we use. I would encourage you to just write the type of athlete they are and to specify that you're looking for a RAMP protocol.

Even our most recent published guidelines for athletes with cardiovascular abnormalities, this was published early in 2025, we really only specifically talk about metabolic testing when we're trying to consider functional testing for athletes.

The different protocols that we'd use are dependent upon what that athlete specializes in. Here at main campus, we actually now have three different modalities. We have the bike for our wonderful cyclists. We have our treadmill for our runners or our triathletes. Now, we have a rower. We successfully completed our first row protocol just within the last week or two. We can really do anything and everything with our phenomenal exercise physiologists on board.

The key thing to remember is that our protocols really should be between eight to 12 minutes. When your patients ask you, "How long do I need to exercise for?", we want to make sure that the test is long enough to actually give validity when it comes to their peak oxygen consumption and for diagnostic potentiation, but we also want to make sure it's not too long where they start to actually fatigue from muscular fatigue rather than their cardiopulmonary endpoints.

In terms of pairing metabolic stress testing and multimodality imaging, actually we have a wide variety in terms of what we can do here. As you know, metabolic stress is obviously going to come with an EKG component, but we can now pair it with other types of imaging. We've been doing echo imaging alongside metabolics for many, many years, and more recently, we've actually started to incorporate nuclear imaging.

I'll get a little bit more specific about this in terms of my use cases for these different types of imaging modalities. I really use echo for my athletic patients for non-invasive hemodynamic assessments when we're looking at valvular heart disease, and certainly when we're looking at obstructive disease such as hypertrophic cardiomyopathy, looking at RVOT obstruction and potentially other cardiomyopathic scenarios. We also use it for congenital heart disease. But I've reached more and more for nuclear imaging when I'm looking for ischemic assessments in my patients, because they have very rapid heart rate recoveries.

So, you can imagine if I've got a marathon runner running on the treadmill, that heart rate recovery between transition from tread over to the stretcher, oftentimes we see their heart rates drop by 20, 30 beats per minute, even in 30 to 45 seconds. Then that test is just useless for me. I've been incorporating more nuclear imaging alongside metabolics.

If you are interested in doing this, the way we have that order now is that you will have to order metabolic ECG stress separate from your nuclear exercise stress order. We'll certainly be in communication when we're able to pair those two together. Any questions about that, find me and we'll certainly help you.

Then finally, we do do metabolic stress in our cath labs, and we can pair it with right heart caths. When I do have concern about exercise-induced pulmonary hypertension or if we're actually concerned about acquired mitochondrial dysfunction, that's something that we can consider.

In terms of guiding my athletes, a lot of times they'll come to me and say, "Hey, doc, what can I do? How much of it can I do? What is my peak heart rate? Is it really 220 minus my age?" [That equation] is faulty. Please don't use that equation. A cardiopulmonary exercise test is the best way to get a measure of what an individual's peak heart rate is. We can certainly use that as well as several other parameters to guide what their conversational pace is. What heart rate is that? Or what is the heart rate at which a pace feels kind of comfortably uncomfortable or similar to threshold?

We can really use a lot of the general parameters from CPET to help develop not only their heart rate zones, but also help give them a guide of perceived effort, which I typically tend to favor over heart rate. These are just some terminologies that I typically go through with my patients with respect to ventilatory threshold, lactate threshold, anaerobic threshold, and much more, which you've heard already about earlier today.

To summarize some special considerations for athletes, so what you've heard about for our congenital population tends to be a little different from our pH population, tends to be different from so on and so forth. That truly holds the same for our athletes. I will typically expect and anticipate my athletes to have predicted peak VO2s greater than 120 to 140% predicted. It's not uncommon for us to see peak VO2s in the 50s and 60s. It's also important, particularly for me, that your peak VO2 is not the same as your maximal VO2. Peak VO2 is really just how hard you could get that day for that, for whatever fueling and hydration you had. Typically, a peak VO2 will continue to rise through the end of a test. If you actually see the VO2 kind of plateau for the last 30 seconds of a test, that's truly their max, physiologically.

Oxygen pulse can also flatten or plateau near maximal exercise in athletes due to this plateau in VO2. That's a little different from individuals whom you may be assessing for stable ischemic heart disease, where we can sometimes see a decline in oxygen pulse in mid to late stress that can indicate ischemia, and as you already know, give us insight into their stroke volume.

Chronotropic index, which is highlighted on our report, typically is between 0.8 to 1.3, but may be lower in athletes, because they're able to get higher VO2s at lower heart rates. This really demonstrates efficiency, not incompetence.

Athletes also are trained to have larger lung volumes. They can generate larger tidal volumes and minute ventilation, and that definitely exceeds our sedentary individuals. Respiratory rates can also be much higher. We can oftentimes see breathing rates of 60 to 70 breaths per minute, which is normal. Then, breathing reserves may also be "low" in athletes alongside their high VO2, and that's because they are able to, again, utilize most of their lung capacity.

Finally, Ve/VCO2 slope or ventilatory efficiency should be measured through the respiratory compensation point. These are more, I think, important for all of us who read and interpret metabolic tests. We really want to avoid calculating that slope through an exercise because athletes do have this profound hyperventilation that I was alluding to after the respiratory compensation point, so it would just otherwise be incorrectly abnormal.

So, in summary, metabolic stress testing is highly advantageous. It's my flavor of choice, and certainly, I encourage you all to really utilize it. I agree it's very much underutilized. Choose the appropriate exercise modality and protocol to achieve an optimal stress test result. Please aim for max effort, not heart rate, in your labs. If you have any trouble with that, please then send them my way and we can certainly help you. Then consider pairing stress testing with echo, nuclear imaging, or invasive hemodynamic assessment if it's helpful for diagnostics. Thank you.

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