Karthik K. Linganathan, MD: Hi, everyone, welcome to the program. I am Dr. Karthik Linganathan. I am a medical director at AstraZeneca, and I’m here to talk to you about the spectrum of heart failure. Now recently, multiple societies joined together to recreate and redefine heart failure. So, what the purpose was a universal definition of heart failure. You know, it proposes that it’s a clinical syndrome with symptoms and signs and could either have structural abnormality or dysfunctional cardiac abnormality, and you should have corroborating findings like elevated NT-pro-BNP or BNP and should have objective evidence of pulmonary or systemic condition.
Now, the categories of heart failure in three categories. One is HFrEF. Now there is HFmrEF and HFpEF. HFrEF is any patient with heart failure having ejection fraction less than 40%. HFpEF is greater than 50%. HFmrEF, which is also now renamed as heart failure with mildly reduced ejection fraction as a category of 41% to 49%; it’s a category in between.
Now, let’s look at heart failure as a burden of disease. Now, we know that there are almost 64-million people who have heart failure, and the projected increase is almost 24%. What’s striking is the 5-year mortality, it’s almost going to be 50%. If you look at even our data, you know, in terms of medical data in patients over 75 years of age, we will actually see that mortality even goes up to 75%. The mortality risk is similar to other common cancers in both men and women. That’s something very striking to remember because we know, we don’t just connect that, but it is very true. It is very similar some of the common cancers. Now what we’re going to see is that over 50% of patients who are diagnosed with heart failure are patients with heart failure with preserved ejection fraction.
Now, you see the bar graph on the left side. You see two bars, and they’re different time period. One is from 1985 to 1994. The other time period is 2005 to 2014. The way to read it is if there are 100 patients you have with heart failure, based on ejection fraction, how do you categorize them? What percentage is each category between HFrEF, HFmrEF, and HFpEF. You would see back in 1985 to 1994, it was predominantly HFrEF. Slowly you see on the right side, in 2005 to 2014, the blue bar is much higher, indicating that patients with HFpEF are increasing numbers.
Now why might that be the case? A couple of reasons: 1) Increasing life expectancy. There is rapidly aging population, and we know aging population, as we are going to see, have a higher rate of HFpEF, and aging population correlates with increased comorbidities.
Now, we also have increasing cardiac and noncardiac comorbidities, right? Whether it’s obesity or metabolic syndrome or diabetes, we see increased rates of atrial fibrillation, which drives HFpEF, and there is improved survival of patients’ coronary artery disease. Previously coronary artery disease used to predominantly cause just HFrEF. Now we see the increased survival, so they start to migrate into the HFpEF category as well.
Last but not least, there is increased clinical recognition. Whether it’s diagnostic techniques or the guidelines which are constantly being, you know, reflects the need for early diagnosis and techniques to early diagnosis as well.
Now, there is growing burden of heart failure hospitalization. You know, I don’t want to go through every statistic here, but, you know, on the picture whether in different parts of the world in US, you see the mean person cost for a single heart failure-related hospitalization is $14,000, roughly.
Also note that hospital admission for heart failure projected to increase almost 50% over the next 25 years. It’s not just the financial costs, it’s the morbidity content that’s going to significantly increase in a heart failure patient.
Now, when we talk about hospitalization, we want to understand the link between hospitalization and mortality. We know that once the patient is hospitalized in heart failure, the mortality clock, so as to speak, actually starts. Meaning in a year after hospitalizations almost 40% mortality, in five years there is almost 75% mortality in certain groups and certain population.
What we see here is, when we talk about readmissions, all-cause readmissions and all-cause death, and you see different colored bars, between one or maroon bar is indicating HFrEF with the blue bar indicating HFpEF. You see, heart failure readmission is somewhat higher in HFrEF, but all-cause readmission is somewhat higher in HFpEF. There is a rationale for it. In patients with HFpEF, sometimes get misdiagnose with other conditions so they can come in sometimes all-cause readmission. But what is more striking is all-cause death. It’s significantly higher, but it's almost similar between HFrEF and HFpEF.
Now, let’s look at pathophysiology heart failure in HFrEF and HFpEF. If you look on the left side of the screen you see a heart model that actually indicates HFrEF. We know that almost 60% of the patients with heart failure with reduced ejection fraction have coronary artery disease, and it probably is a primary etiology for HFrEF. So, the majority of those patients end up having an ejection fraction of less than 40%. They have dilated left ventricle, and obviously they have abnormal contractility. They also undergo remodeling because of increased RAAS and neurohormonal activation, and at least further remodeling.
Now, let’s come to the right side, HFpEF. These patients have an ejection fraction greater than 50%. There is no clear LV dilatation. They have, you know, constant recurrent symptoms eccentric hypertrophy, but they have normal contractility. Not normal contractability based on ejection fraction, but with newer techniques we have also seen that they have some amount of systolic impairment which is not noted in echocardiogram. So, they have some amount of diastolic dysfunction in other categories and also have possibly some systolic impairment, but documented as normal contractility with ejection fraction greater than 50% on echocardiogram.
Now, when we talk about comorbidities. Comorbidities happen with both HFrEF and HFpEF. Let’s stick to the box in the middle which shows obesity, hypertension, type 2 diabetes, and kidney disease. You can see they can cause both HFrEF and HFpEF. Now, with HFrEF, for example, the hypertension. Hypertension causes increased, uncontrolled blood pressure causes some kind of nonischemic cardiomyopathy leading to HFrEF.
Now diabetes can do the same thing. Diabetic cardiomyopathy, if untreated for a long period of time will actually be HFrEF. They also can cause HFpEF. In HFpEF there might not be just associated comorbidities. We’re going to see how they make them; they are actually driving factors to cause systemic inflammation and cause heart failure with preserved ejection fraction. So, when we look at these comorbidities, we don’t see this comorbidity just associated with those HFpEF. We see them as driving factors to cause the systemic inflammation, which causes and progresses HFpEF.
Now, what we want to understand with HFpEF, it’s a systemic syndrome. If you look at the box on the left side, you’re going to see four of those comorbidities as listed here, which is obesity, hypertension, type 2 diabetes, and renal insufficiency. All these comorbidities are not just having passive relationship with HFpEF. They actually actively induce systemic inflammation. The systemic inflammation will lead to changes in all the organs in the body. You know, in the heart it causes myocardial remodeling. We’re going to look closely at what happens with the heart. It
also causes pulmonary changes, chest wall changes. It causes pulmonary hypertension, pulmonary vasculature changes. It causes different renal sodium retention and handling. It also causes changes in skeletal muscle, oxygen extraction, and we’re going to look a little bit closer, and also diaphragmatic muscles and the muscles in your chest cavity leading to symptoms as well. It causes changes in all the organs. Now, when we look at the heart, what it does is systemic inflammation leads to two pathways. One, it leads to you’ll see increased VCAM and E-selectin. These lead to increased leukocyte migration and fraction. Increased leukocytes will lead to increased TGF-beta production. Increased TGF-beta production will lead to increased collagen formation. So, it increases collagen.
Now, on the same diagram, you’ll actually see that the same systemic inflammation will lead to decreased nitric oxide availability. This leads to decreased soluble guanylate cyclase, leading to decreased cyclic GMP availability and decreased PKG availability. This leads to hypertrophy in noncompliance. So, when you think of cardiac myocardial remodeling due to systemic inflammation that is set into motion, you actually lead to increased collagen, increased hypertrophy, and noncompliance.
Now, when we think of HFpEF, we set a systemic syndrome, and the systemic syndrome causes changes in different organs. We’re not going to go every one of them, but I just want to point out, for example, in lungs it causes chest wall restriction. It causes pulmonary hypertension. The heart, we already saw what changes it causes and leading to changes in increased filling pressures and volume overload or preload and increased afterload. In the liver it can cause NASH, and in the kidney, it can cause glomerulomegaly and glomerular dysfunction and skeletal muscle changes as we talked before. So, it causes all those changes, and in each patient these changes in different organs might be at different levels.
So, when we think of HFpEF, it has very different phenotypes. A lot of phenotypes based on pathophysiology, because you can actually imagine the same patient with HFpEF based on which organs and how much involved. You can have different ways they present, different symptoms they may actually have, and different organs will also drive different symptoms and signs. So this is a bigger reason why HFpEF has different clinical and pathophysiological phenotypes, making it sometimes challenging to diagnose and treat.
So, what about comorbidities. There are many noncardiac comorbidities that are prevalent both in HFrEF and HFpEF. In HFrEF patients, almost 84% of the patients have at least one comorbidity. In HFpEF, almost 94% of patients have at least one comorbidity. What is striking, what we’re going to see here, is it shows different comorbidities and different colors. The blue color showing HFpEF patients, the maroon color showing HFrEF patients. The percentage of prevalence or incidence of these comorbidities in those patients, what is striking is diabetes and CKD are on top of the list in terms of comorbidities. We also saw these comorbidities as just not being an associated comorbidity but sometimes driving factors.
In diabetes, almost 30% to 35% of the patients would be in the heart failure categories have been usually diabetes and similar with CKD it is higher, between 48% to 56%.
What do we normally see, when we think of HFpEF, which kind of patient are we normally thinking? It’s normally older patient and normally female. Why do we think that? Let’s look at the bars on the left side. You’ll see that in patients with HFrEF, the average age is around 68 to 69, and with HFpEF is around 78 or so. We kind of understand the rationale for that, because with HFrEF it’s led by coronary artery disease, so these patients already have some kind of cardiac event and subsequently lower ejection fraction in HFrEF.
With HFpEF, these patients have, as we saw, multiple comorbidities as they start to age, and these comorbidities will start to drive the systemic inflammation in HFpEF. What about female gender? We see in female gender it is more common in HFpEF patients, like almost 46% of the patients compared to HFrEF.
There are fewer conditions in HFrEF which are very female gender-oriented, which is like postpartum cardiomyopathy or spontaneous coronary dissection, but the majority of HFrEF being driven by coronary artery disease is common in males, but in HFpEF you see more female gender predominance. One of the reasons could be the systemic inflammation and the associated stress that happens with systemic inflammation. The heart in female patients might actually, you know, adjust to the stress by different more like concentric hypertrophy rather than just dilating. So they may present more as HFpEF. That could be one of the rationales why HFpEF patients have more common female genders.
What we want to see here is we looked at diabetes. We saw how diabetes and CKD is very common in HFpEF patients, and we also saw how diabetes and CKD are individual drivers for especially HFpEF. But what we also want to note is the connection between heart failure and CKD, the cardiorenal syndrome or the cardiorenal connection, which one organ, you know if it’s the heart, by its interaction with the kidney can actually make the kidney worse, and the kidney subsequently by its interaction we’re going to look at more closer, will make the heart failure worse. Diabetes, what actually we’re going to see is a driving factor for both heart failure and CKD. Almost 24% of the patients with diabetes have heart failure as the first complication.
I think it could be even more common because diabetic cardiomyopathy is somewhat underrecognized and undertreated, and 58% of the patients with diabetes develop CKD. Diabetes is the common driver for heart failure and CKD.
Now, let’s look at it more closely. In a patient with diabetes, there are multiple things that happen which can drive both heart failure and kidney disease. Altered cardiac energetics, hypervolemia, increased sodium retention, inflammation, ischemia, neurohumoral activation, RAAS activation will drive both heart failure and kidney disease. And diabetes also has direct organ changes, diabetic cardiomyopathy, for example, causing heart failure. So, you see how diabetes drives both heart failure and CKD, and more importantly, the next step to it is once the process starts, and when you have patients with heart failure, and because of cardiorenal infraction and cardiorenal syndrome, it also worsens kidney disease.
Let’s look at it much closer now. You’ll see the box in the top, which is called cardiorenal connectors, meaning that once either of these organs have a disease process you’ll have activation of multiple systems. One is RAAS activation, one is oxidative stress, one is increased inflammation, and one is sympathetic nervous system activation, meaning that it is present when either of heart failure or chronic kidney disease is present. Once this process starts, each of those organs start to get worse.
Now, when the heart failure starts to get worse, you have cardiorenal syndrome, which is because of low cardiac output, increasing inflammation because of the heart failure, because of chronic hypoperfusion or increased venous pressure, or increased glomerular pressure or increased venous resistance. The kidney, subsequently also thinks ahead, meaning that what starts as normal kidney because of hypoperfusion, increased venous pressure, and so on and so forth, will have glomerular changes, increased sclerosis, fibrosis, leading to initiation of kidney damage and progression and worsening of chronic kidney disease.
What happens is the patient has CKD. The CKD leads to anemia, metabolic abnormalities, and volume overload, and thereby it worsens heart failure. What you see here is once the process is set in motion, there is a clear cardiorenal connection one system unfortunately, you know, leads to worsening of the other organ and the other organs and so on and so forth to the heart failure. So, that’s what we see here, the cardiorenal connection.
We said, okay now theoretically that makes sense. What about, do we really see it when we look at data, right? Let’s see on the left side. We note increased incidence of heart failure in the patients with CKD compared to patients without CKD, showing the heart failure and a CKD connection, right? The red, if you see the HFrEF graph, you’ll see the y-axis is cumulative evidence of heart failure, the x-axis, time in period. The read or maroon line actually indicates patients with CKD and the blue line indicates patients without CKD. You see, the patient with CKD almost has twice, you know, higher chance of having heart failure, whether it’s HFrEF or HFpEF.
What about, once you have heart failure, what happens to CKD, the other part of the cardiorenal connection. Once you have heart failure, you notice that there is increased prevalence of rapid GFR decline. You know, you compare the two graphs, the violet graph, which is no heart failure. You see, you know, lower prevalence of GFR decline, but patients with heart failure there’s significantly two to three times higher problems with GFR decline, meaning the higher or worsening progression of kidney disease.
Now, what about diagnosis. So once we have risk factors, symptoms, signs, then you start to suspect that it is heart failure. Obviously, if you remember the universal definition, there needs to be other corroborating factors. The other corroborating factor could be elevated NT-proBNP. Once that is established, then you want to now think of how you classify, whether it’s HFrEF, heart failure preserved ejection fraction, or heart failure mid-rate ejection fraction, so you obviously do an echocardiogram. You subsequently confirm that heart failure, and subsequently you categorize that. Then, you also think of what could be the etiology, comorbidities, and driving factors that also need to be looked at for each one of them.
Now, we looked at this before. So, if the ejection fraction is less than 40%, and the patient has signs and symptoms of heart failure and corroborating factors like we saw before, then they have heart failure with reduced ejection fraction. When they have greater than 50% and signs and symptoms of heart failure as heart failure with preserved ejection fraction, HFmrEF or heart failure with mildly reduced ejection fraction when the EF falls in the category between 41 to 49.
Now, we might say this is not a dynamic process, it’s a very static process. You’ve got diagnosis that are in the same category that is not really true. Even a single patient you might migrate between those different categories. You might be in HFrEF and you might recover, you might become HFmrEF or a mildly reduced ejection fraction. You might even recover and still might have heart failure symptoms. You might slowly progress into the other category HFpEF. Similarly, you might also get worse.
Now, what are the factors that make it get worse. For example, the simplest would be diabetes. You might initially be HFpEF, but as it progresses and inflammation and sodium retention, neurohormonal activation keeps progressing, you might actually have slowly the ejection fraction might drop, and your diabetic cardiomyopathy can progress, leading to HFrEF.
What factors normally lead to recovery? You know, younger age, females, lower heart failure severity, shorter heart failure duration. You know, fewer comorbidities, obviously this will help, obviously, the recovery process, moving through the spectrum between HFrEF and improving to normal ejection fraction along the way. So, these are not static categories. They are dynamic, and they change.
So, we looked at HFpEF. We looked at how HFpEF starts as a systemic syndrome, how it affects multiple organs, not just the heart, and each organ has manifestation, and each organ has its own set of symptoms and signs that it can produce, and now you understand how HFpEF diagnosis can become challenging based on which organs are involved or how many organs are involved and how many signs and symptoms come to the organ you can have, you know, a patient who can be considered asymptomatic but fully is symptomatic. They have further intolerance. Two, the patient has full-blown, you know, increased lower extremity edema with severe shortness of breath and cannot get up from the chair.
The number one problem is there is no single objective marker. Like we talked about, there are different clinical phenotypes. There are different driving factors that cause those phenotypes, and there are multiple comorbidities that can act as HFpEF mimickers or can cause symptoms that mimic HFpEF or construe as HFpEF. What do I mean by that? For example, you can have CKD. The patient probably is in HFpEF, but sometimes the volume overload can be attributed to CKD, meaning that sometimes we assume they are different, we treat them different, not considering that it’s actually truly HFpEF. It’s seen, and it’s known, that BNP levels are normally lower in HFpEF. So sometimes they fall below the diagnostic threshold that we normally set, and we might not diagnose HFpEF until later.
And there are complex and limited predictive capabilities of echocardiogram. Unlike HFrEF where you get an echo, you say the ejection fraction is low or it’s great, we diagnose it, in HFpEF, it’s not that simple. There are multiple categories of diastolic dysfunction and pressure changes that you actually have to look at and say yes, now this patient is in HFpEF. The last but not the least, in HFpEF, there is underuse of provocative testing. What we mean is underuse of diastolic stress test, if it’s an echocardiogram as a stress test, or underuse of cardiac catheterization with a stress cardiac cath. Seeing, you know, changes in pulmonary pressures, another function as you do cardiac tests. There is underuse of provocative testing.
So, says how we see there is increased incidence and prevalence of HFpEF as you go through it, based on multiple reasons, and how we see it’s diagnosis is a little more challenging than HFrEF.
So, the signs and symptoms, do they differ between HFrEF and heart failure preserved ejection fraction? The answer is absolutely not. The signs and symptoms really don’t change. The only things that might actually change and how the patient and how clinicians, when they diagnose those signs and symptoms might actually change, meaning patient with HFrEF, you know, both the physician and the patient might be more heightened by those signs and symptoms and ability to diagnose it earlier, come back to HFpEF, and the patient is older, has comorbidities. You might view and attribute those symptoms to something else, you know, such as age or maybe it’s just diabetes or maybe it’s obviously just weight gain. No matter what it is, it gets attributed to that leading to non-early diagnosis, leading to a longer time before we diagnose, and also leading to a lot of misdiagnosis loop before the patient ends up getting diagnosed with heart failure and preserved ejection fraction.
Now, this is from the Optum database. They looked and said where do we really diagnose heart failure. Almost 40% of the time, the diagnosis of heart failure is only in an acute care setting. What is more striking is, almost 50% of those patients had potential heart failure symptoms that could have been diagnosed before. (25:26) goes back to the point of where, you know, there is a heightened sense to look for those signs and symptoms to diagnose that. And, in women and black patients, 11% to 18% more likely to be diagnosed only in an acute care setting rather than in an outpatient setting. That also brings the gender patient bias that unfortunately goes into those diagnostic processes.
So, let’s look at what are the identifying opportunities for timely diagnosis for heart failure. The first is screening, right. One is identifying those patients with asymptomatic or nonspecific symptoms more common in HFpEF. This also brings into context of your pre-heart failure, the Stage B heart failure status where it exists and maybe they have nonspecific symptoms, and you want to be able to screen and diagnose. For early diagnosis, that’s where it is.
The next is, you also want to avoid loops of misdiagnosis, which is more, unfortunately, and firstly, it’s more common in HFpEF, leading to longer period of these patients being in outpatient setting, not being diagnosed, and end up in the hospital and subsequently unfortunately being diagnosed there. And the third step, which also is an important opportunity, is once diagnosed, getting them an appropriate and ideal treatment that needs to be done for it. And obviously, it goes without saying, once they’re diagnosed, they get hospitalized, they get discharged, appropriate monitoring and titration is required to prevent rehospitalization. Because what we saw is one in eight deaths in general is related to heart failure, and once hospitalized, the risks of mortality increase almost 40% in the first year and almost 75% in five years. So, it’s important to prevent even this first hospitalization.
So, there is adequate opportunity for patient awareness, education, enhancing knowledge of diagnostic criteria as we saw the challenges in HFpEF and what we need to overcome to diagnose the patients earlier, and more importantly collaboration. Because especially in HFpEF where these patients see multiple physicians, being heightened to those signs and symptoms, not just attributing to those comorbidities, but using the signs and symptoms, using appropriate markers to diagnose the patient is very important and develop standardized protocol. Once they get diagnosed, an early diagnosis, the standardized protocol is how they get circulated to other specialists to treat not just their heart failure, especially relevant in HFpEF. Also, there are comorbidities to help in reducing both morbidity and mortality in these patients.
Thank you everyone, and you know you can put your questions in the chat if you’re not done so far. We will be happy to go through them.
Female: Thank you, Dr. Linganathan, for that comprehensive overview. Again, if you have any questions, I know we are up against some tight time here with about a minute left, so if you do have one feel free to drop it into the chat. We’ll give it a couple of seconds. And seeing none come through, thank you again, Dr. Linganathan, and this will conclude today’s session.
Linganathan: Thank you.
Karthik Linganathan, MD, FHFSA, MBA
Senior Medical Director
US Medical Affairs
*Understand the Burden of Heart Failure
*Discuss the Pathophysiology of Heart Failure including systemic syndromes, co-morbidities, and inter-relatedness of HF, CKD, and T2D.
*Discuss the diagnosis of HF including HFpEF and sex differences/healthcare disparities.
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