Dr. John Giaconoa (UT Southwestern Medical Center): So moving to Fundamentals Part 1: Lifting the Veil on ATTR-CM Biology, Disease Burden, and Clinical Clues. And I will pass it to Jill Waldron.

Jill Waldron (Huntsman Cancer Institute): All right. Well, thank you so much. It is great to be here. Thank you so much for having me. It is great to be here today, and I am especially happy to present to other APPs. I do think that each of us is in a unique position where we can find these patients and that you are going to be the front line. We have lots of referrals that come from APPs, so hopefully you will find some new things today that you will be able to take back into your practice.

[00:06:56]

Specifically, we want to make sure that you understand the pathophysiology of amyloidosis and you understand the different etiologies so that you can find different ways to distinguish other types of disease processes from amyloid, that you can work to help your patients feel better, that they can get on good treatments, and that you can understand the tests that they are using to work up their diagnosis as well as to monitor them over time.

And to use up-to-date types of research and practice that you can bring back to your areas, that you can help educate not only the patients but others that you work with, whether it be in a multidisciplinary care, whether it be a shared practice among an academic center and a community center, and that you can communicate, in a professional way, with difficult decisions, difficult discussions that patients with amyloidosis need to have and need to understand.

[00:08:12]

First of all, I just wanted to address what is amyloidosis in general. So amyloidosis is basically extracellular tissue of highly ordered fibrils, and we know currently of over 42 different types of amyloid proteins out there. These are basically fibrils from misfolded proteins and they can affect various different disease processes.

[00:08:39]

Within the heart, there are 2 different types, and the one we are going to focus on today is the ATTR type and specifically how it affects the heart. So transthyretin stands for transporter of thyroxine and retinol, and it is the protein that is produced mostly in the liver, that is the main manufacturer, but somewhat also in the retina and the choroid plexus. And it circulates as a tetramer and then as it becomes dissociated, then it can release into 4 different monomers and then these monomers will misfold and then they will accumulate and make different amyloid plaques that can go on to create disease.

And I will show you a way that I explain it to my patients in just a minute. So of these 2 types, we know there is a wild-type ATTR and there is a hereditary type, and typically we associate the wild-type with aging. It is usually found in the last 2 decades or so of life, over age 65, and the hereditary type is usually caused from a genetic mutation that they are born with.

And we know of over 130 different TTR mutations currently. In the United States, the Val122Ile, or we also call it the VAL122I is the most frequent one that causes cardiac disease.

[00:10:16]

So this is just a graph of the pathophysiology of the ATTR proteins. So the liver is again the manufacturer, and I make this little picture with my hands to the proteins. So we have our 4 little tetramers or 4-leaf clovers, and this is transporting thyroxine and retinol through the bloodstream. But then, for some unknown reason, whether it be a mutation or aging or something, these will separate into 4 different monomers, and then if this is one monomer, it misfolds and when that monomer misfolds then it is not functional anymore.

It does not transport anymore, and then it accumulates or aggregates with other misfolded amyloid proteins, and then they can make bigger sheets and make amyloid sheets, and those will deposit in different areas of the body. In the heart, it can lead to heart failure and restrictive cardiomyopathy. In the nerves it can show up as neuropathies or autonomic conditions.

[00:11:23]

So this is just an example of you having different types of these misfolded proteins coming together in a spatial configuration that can make abnormal disease process.

[00:11:36]

So the most common subtypes, there are usually recognized only 2 types that affect the heart. There is technically a third, but 98% of them are either light-chain or TTR type, and they are both prevalent, and we need to separate them because on testing they do not necessarily look the same. You cannot tell one from the other. So we will talk about diagnosis, but these can also separate out. Again, the transthyretin type can be a variant or a hereditary type or the wild-type.

[00:12:14]

It is pretty common, more common than we think. We have been taught that this is a rare disease, but studies show it is probably more common than we think. A lot of doctors and providers did not learn about this in medical school, and we are learning more as time goes on, so we want to make sure that communities are educated. But if you were to take all heart failure with HFpEF over age 60, you would find that about 6% of them have a TTR cardiomyopathy.

And if you were to take that group of them and you were to look at ages over 60 who are hospitalized with heart failure, you could find anywhere from 10-15%, on average about 13%, who also have cardiac amyloidosis. So those are pretty big numbers to help us realize that we just really need to look for it, and it is probably right there under our noses. Those of you that may work with TAVR patients in the structural clinics or doing transcatheter aortic valve replacements, you may also come in contact with these patients more frequently than you realize.

So it has been estimated that up to 16% of these patients can also have cardiac ATTR. And those are just for the wild-types. The hereditary types we are not sure as much, although there are more mutations that we are still finding.

The most common ones are the 7 listed below: Val122I, Thr60, the Val30Met. And to be able to determine if it is a hereditary or wild-type, you need to do genetic testing.

[00:14:10]

This is a picture of just the prevalence and incidence of cardiac amyloidosis throughout the world.

Just to give you an idea that this is a worldwide problem. And in the United States, we may have even more that we have not found. But if you look back in other countries, they have an even higher incidence that they have been treating for some time now.

And these are just some of them from Europe and Japan. But when we go to these international amyloid conferences, you will see patients and providers and doctors from all over the world, in Brazil and different countries, that are really working on research and treating patients.

[00:15:00]

The burden is high. The burden affects the patient's quality of life as well as affecting their caregivers. So the most common side effect that we often hear patients say is that they are just so fatigued. And it is different than the typical heart failure fatigue. Everyone who has heart failure has fatigue. But they have this intolerance with activity, and they just feel like they just cannot exercise like they once used to. And they may have been really great athletes at one time. Something is different now. They also have issues with insomnia. They also have issues with fluid retention.

And their caregivers have a lot of anxiety over this. They do not know a lot about it. They are not sure who to go to learn about it and what kinds of things they need to do to help their loved ones.

And those that have the genetic mutations often worry about their siblings, their nieces, their nephews, their children, their grandchildren, and how it is going to affect them both financially and health-wise.

[00:16:16]

So just to give you an idea of some of the physical burden that patients have reported, this is broken up between New York Heart Association class I-II and New York Heart Association class III.

But looking at this study with 208 patients, you can see that 127 of them reported that they were unable to walk normally. And about 59% we had in 3 months were not able to participate in some of their social or leisure activities that they were normally a part of. And 55%, the inability to complete household chores within 3 months. So that affects where they can live and what help they need. Family members had to do it for them, about 63%. And then the median time to take to get their chores done was about 3%.

And then if you look across from the classes, you can see that the higher their New York Heart Association class, they needed more help from their caregivers. It took them longer to get things done. They were not able to participate.

So severity of the disease matters as well.

[00:17:38]

This is also looking at New York Heart Association symptoms. So if you look at the red line, that represents all patients. And then the blue line, class 1-II, and the black line, class III. And you can see these cardiac symptoms on the left side. All of them are worse by New York Heart Association class III. But all of them have these symptoms as well. So heart failure, shortness of breath, AFib, fatigue, swelling, edema, heart palpitations, weakness in their legs, gastrointestinal urinary problems, orthostatic symptoms, and low libido.

So we want to catch this early. We want to find this, where we can help them.

[00:18:24]

There are some differences with the genotypes and phenotypes. So looking at the 3 most common ones, the Val30Met, the Val122I, and the Thr60, they can have either predominantly neuropathic or cardiac features, or they can have mixed features.

So if you were to find someone who had the Val32Met, which is primarily more in Japan and also in Portugal, then you can find these patients, if they are diagnosed early, tend to have more neuropathies. And the late onset ones tend to have more cardiac involvement. Whereas the Val122I tends to have more cardiac symptoms and less neuropathy. They can have a mixed feature as well, though. Interestingly, the Val122I in America is anywhere from 3-5%, on average 4%, are carriers if they are of African descent. And that also includes those from the Caribbean.

In a study of over a thousand patients with TTR cardiomyopathy, those that had the Val122I did not have as long a survival rate as those that had a different type of genetic mutation or had wild-type. And so oftentimes these patients will present very sick and sometimes even need to move on quickly to a heart transplant.

[00:20:02]

So again, there is variability in timing of when the disease can come on with genetic types.

Some patients will have a diagnosis later in life, and certain variants will actually occur earlier and tend to be more severe. But the average age is usually about age 74. I have not seen anyone, I think, less than their 40s, although you can have it as low as late 20s. And sometimes even at age 90 being diagnosed with a new hereditary type of ATTR. Most of the cardiomyopathy patients have just a little bit of soft tissue involvement and not as much neuro as other types of cardiac amyloidosis. And interestingly, about 90% of patients with wild-type are white males.

So the hereditary patients tend to be more in African-American Black descent. The hereditary cardiac amyloidosis also has variability, though, in penetrance. So just because somebody has had the genetic mutation, it does not mean that they will necessarily also develop the disease. And we follow them over time with testing to make sure that we can catch it early. And some of this is influenced by geography, by the age of when the index patient was first diagnosed, and possibly other genetic and non-genetic factors, including where the location of the chain first was found.

[00:21:56]

Okay, so let us talk about symptoms for a minute.

So again, you can have a range of age onset, but usually the wild-type will be later in life. And both diseases are typically found in men. Women can have this as well. Women tend to have more of the hereditary type than the wild-type. But I think part of this is also that we are not looking for women as much. And I think that sometimes we look at different cutoffs for left ventricular hypertrophy or thickness on echocardiograms.

Sometimes I am even now trying to lower that due to body size of women, so that maybe that cutoff is now 1.0-1.1 cm instead of the typical 1.3 cm or higher. You can also see that the duration of time before they can get the diagnosis is years. So it may be 2 or 3 years before they have had symptoms before they find the diagnosis.

And part of this could be that patients are just not being worked out quick enough. And some patients will even have orthopedic symptoms 5-10 years before they will develop cardiac symptoms.

The median life expectancy really changes. So it is typically said to be about 2 to 5 years for the hereditary type and about 4 for wild-type. And then if you have more polyneuropathy phenotype, then it is usually longer. I have to say, though, that there is good news.

This was back in 2020. These days I am seeing patients live longer. The longest I have had though so far with either wild-type or hereditary was has been about 8 years. And that is because we have only had FDA-approved medications for 7 years. So I like to tell patients there is hope and that with new therapies coming out, that hopefully those numbers will change.

If you look at the hereditary patients the clinical manifestations that affect them are yes for everything. For heart, nerves, autonomic findings including their bowels, kidneys, their eyes, and their musculoskeletal. Whereas the wild-type tend to be more symptomatic with the heart and musculoskeletal. Although I do think we are finding more peripheral and autonomic symptoms in wild-type patients these days too.

I think again this was 2020, and we have a neurologist that is finding a lot of orthostatic hypertension and a lot of neuropathies in our wild-type patients as well.

[00:24:48]

These first 3 mutations again are common here. I just want you to be familiar with them.

So Val30Met, if you have the early disease, it tends to be more polyneuropathy. If you have the late disease, it tends to be more cardiac.

And if you have the Val122I, you want to think that this is more common in African descent and their descendants. And that turns out to be millions of patients, by the way. So there are a lot of our fellow African Americans that do not even know about this disease. They have learned about sickle cell. They have learned about lots of other things that are common with their genetics. But they have not learned about this. And so it is a great teaching opportunity to say, "I think because of these reasons we should have you screened."

The Thr60 is definitely a mixed phenotype. But this is more common in the Appalachian, Virginia, Eastern side of the United States as well as those that have an Irish ethnicity.

[00:26:02]

We talked a little bit about how sometimes it can take years to find the diagnosis. I am hoping that we are doing better than 6 years now. Six years is the average delay. It used to be said that it would take 5 to 7 doctors for someone to finally get the diagnosis right. But I think with education that this is coming down to usually about 2 to 3. And I think cardiology plays a big role in that.

I think a lot of our referrals come from cardiology because currently we are the only organ in amyloidosis that can be diagnosed by a scan, not by tissue biopsy. And that will change within time. We are going to have great scans that can pick up all different kinds of amyloid in different places, including Alzheimer's and beta amyloids.

A lot of times this type of amyloidosis is not found until it reaches the heart. And we need to spread education. So you know, patients often are the best at spreading the word to their communities. And you can encourage them as well.

The thing I want you to pick up on is if you are taking care of a HFpEF patient that does not seem like a typical HFpEF with cardiometabolic syndrome that is not obese, diabetic, hypertensive, but maybe is older, thin, has neuropathies, maybe has some restrictive disease, then you might think, do they have these other things? And you can ask some of the other review of questions quickly.

Diagnosing the cardiac symptoms is also challenging because of the mixed phenotype and the vague symptoms. And so you really do have to be a detective.

[00:27:59]

When you do not take the time to think about other possible differentials, it can lead to a long time before they are diagnosed with more severe disease. They can have inappropriate treatments. I have seen some patients who are diagnosed with hypertrophic cardiomyopathy get actual surgery for myectomies that later kept growing and ended up being TTR. You can have anxiety and distrust in the health system, unneeded hospitalizations, and poor quality of life.

[00:28:32]

So let us look at the red flags. This one is probably one of the most important things I think to point out. So I am going to summarize it by telling you the 5 big red flags, but then I want you to look carefully at some of the different imaging and testing, specifically cardiac-related, that you can look at. I tell patients and other providers all the time, you want to look at the red flags, but you also need to have at least something that is objective before you trigger the workup because the symptoms can be nonspecific.

So the first one on the clinical symptoms, I think, is heart failure. So that typical HFpEF that does not seem to have the normal cardiometabolic syndrome. And then if they have syncope, but it is not ventricular tachycardia, it is maybe more like orthostatic hypotension. Third, if they are having conduction disease like AFib or some blocks, most of them will end up with a pacemaker at some point. Those are the big 4 ones.

And then I would add in the fifth red flag, would be bilateral carpal tunnel syndrome. And it is bilateral, it is not unilateral usually. Sometimes if you catch it early, it is unilateral first. But if you have the other 4 cardiac ones, it is usually bilateral. And the sixth would be lumbar spinal stenosis. And if you have those big red flags, then what I would say is look at the EKG. Do you see is the EKG showing low voltage? Is it discordant with the amount of LV wall thickness that you are seeing? Is there a lot of grade 2/3 diastolic dysfunction that is showing restrictive cardiomyopathy? And then looking at the cardiac MRI and then looking at the labs. And we can talk about some of those today too.

[00:30:36]

You have to have the suspicion first because it will not just jump out at you unless it is severe. So unexplained left ventricular hypertrophy, you can even have angina. You can have ischemic cardiomyopathy at the same time that you have infiltrative cardiomyopathy. So do not just say, "Oh, we have we have got our ideology, I am not going to work this up."

If you have aortic stenosis that is specifically low flow, low gradient, or if you have that impaired longitudinal strain on your echo, those are red flags. And then, again, the carpal tunnel syndrome and peripheral neuropathies.

[00:31:18]

We talked about how hypertrophic cardiomyopathy is often mixed up. I can tell you at our center our hypertrophic cardiomyopathy clinic orders more pyrophosphate scans than we do. And that is because they need to make sure that they have the correct diagnosis. Sometimes patients with left ventricular hypertrophy and high blood pressure will also have increased wall thickness. A typical patient of this could be someone of African-American population, and you might miss it.

Over time they are on lots of blood pressures, but then when they start to get into their 50s, they are backing off their blood pressure medicine and they actually have ATTR as well, even though they had hypertension in the past. Diabetic neuropathy sometimes can mimic this. So if you see neuropathies and they do not have diabetes, that should be something to catch your attention.

The carpal tunnel syndrome, we ask everybody that now if we are thinking about it. And then sometimes there are rare things like Anderson Fabry or Charcot-Marie-Tooth disease.

[00:32:21]

This is the algorithm that is proposed recently in 2025 to work up this diagnosis.

The tests are here on the left in the blue, and we will just go through these. The first thing you have to do is rule out light-chain amyloidosis because it is a cardiac medical emergency if you miss it. And again, looking at the echo and the cardiac MRI, you cannot tell the difference by just looking at the imaging.

You have to draw the free light-chain labs and the immunofixation labs. If they are positive or if you do not know how to read them, you need to refer them to hematology. And they have to have some tissue biopsy to rule that out because that is the only way you can get that diagnosis of light-chain amyloid.

However, if those all come back negative, you are good to go, and you can order some type of bone scintigraphy scan. Usually a PYP scan. Some people do DPD. If grade 2 or 3 come back positive, you have got your diagnosis, and you move on to genetic testing. If it is zero, it is pretty unlikely that they have amyloid. I do not tell them that they do not have amyloid at all, and it is ruled out. I tell them you do not have amyloid in your heart. Because in a few years maybe some of those symptoms can turn into cardiac symptoms. Grade 1, if it is still suspicious, you could order a cardiac biopsy, and sometimes we have done that. And their PYP was negative, and the biopsy was positive.

[00:34:00]

And then the World Heart Federation also came up with an algorithm a couple of years ago that that describes this very similarly.

If this is a one you want to snap a picture of, again, I would highlight that you have your suspicion in your history, but you do have at least 1 objective finding, whether it is from EKG, echo or cardiac MRI, before you start the workup, and then you rule out the light-chain. If there is anything abnormal, you send it to hematology, they have to get tissue biopsy. If they are all normal, you do the PYP scan or bone scintigraphy with spectrometry. And then if it is grade 2 or 3, it is positive, you do genetic testing. And if not, then you have to decide, do I want to retest again maybe in 3 years, or do I want to get a heart biopsy, and it is shared decision-making.

So that is it for this first part, and John, will turn it back to you.

Dr. Giaconoa: Thank you so much, Jill. I really appreciate all of that very good information. And every time you say orthostatic hypotension, my ears pop up because I have found a couple of patients that have been sent to our clinic with autonomic dysfunction, and it turns out that they have ATTR cardiomyopathy. They can be sent in from blood pressure specialists too, so there is an overlap.

[00:35:26]

All right, so moving to our case.

[00:35:28]

So this is Mr. Smithson. He is a 72-year-old man. So this is the patient who is just getting older. Mr. Smithson is a Black retired engineer, has never used tobacco and drinks wine socially. He has a long-standing history of hypertension, bilateral carpal tunnel syndrome, he had surgery 7 years ago, lumbar spinal stenosis and mild CKD stage 3a. He is currently on amlodipine and chlorthalidone. Chief complaint: he is mentioning worsening shortness of breath with walking, leg swelling, and increasing fatigue over the past 8 months.

Mr. Smithson says he becomes short of breath when climbing a single flight of stairs, which is something he easily could do a year ago, and he reports no chest pain but notes a heaviness and some rare palpitations. He sleeps with 2 pillows, says that he has numbness in his feet that he blames on getting older. He has worsening swelling in his ankles and feels weaker than usual.

[00:36:34]

Poll 3: Which feature of this patient’s history should most increase suspicion for ATTR-CM?

Audience, we have a poll question. Which feature of this patient's history should most increase suspicion for ATTR cardiomyopathy?

1. Hypertension;
2. Bilateral carpal tunnel syndrome;
3. Mild chronic kidney disease; or
4. Occasional palpitations.

[00:37:18]

Patient Case 1: Physical Examination

Coming back to his physical exam, his blood pressure was 128/70. Excellent. Very good, very controlled. Heart rate was 88, and his oxygen was sitting at 97%. Cardiovascular focus exam, jugular venous distension 10 cm, S4 was present, and no murmur.

Pulmonary had bibasilar crackles. In his abdomen, he found some mild hepatomegaly, and in his extremities 2+ pitting edema. Neuro exam showed decreased vibratory sense in his feet, and other findings included thickened and slightly atrophic skin over his shins.

[00:38:04]

Patient Case 1: Initial Investigations

Continuing on with some initial investigations. On EKG, we saw low QRS voltage in limb leads, pseudo-infarct pattern in precordial leads and first-degree AV block. Blood work showed troponin was mildly elevated. NT-proBNP was very elevated. SPEP/UPEP was normal. Alkaline phosphate: mildly elevated.

On echo he had severe concentric LVH with small LV cavity. He had a preserved ejection fraction of 55% but impaired longitudinal strain with apical sparing pattern by atrial enlargement and mild to moderate pericardial effusion.

[00:38:44]

Poll 4: Which of the following is most associated with the discordance between his ECG and echocardiogram?

1. Hypertensive heart disease;
2. Hypertrophic cardiomyopathy;
3. Restrictive pericarditis; or
4. Transthyretin amyloid cardiomyopathy.

We have a few more polls, so please bear with us.

[00:39:30]

Poll 5: Mr. Smithson’s ancestry is relevant because which subtype of ATTR-CM is most common in this population?

1. AL amyloidosis;
2. Dialysis-related amyloidosis;
3. Hereditary ATTR associated with that V122I variant; or
4. Wild-type ATTR only.

We will move on to the next poll.

[00:40:17]

Poll 6: Which diagnostic test should be performed next to further evaluate for ATTR-CM after ruling out AL amyloidosis?

1. Cardiac catheterization;
2. Endomyocardial biopsy (first-line);
3. PET scan; or
4. PYP scintigraphy.

We have 1 more poll before I will pull our faculty in for some discussion.

[00:41:02]

Poll 7: Which extracardiac feature in this case is a known early clinical manifestation of ATTR-CM?

1. First-degree AV block;
2. Lower extremity edema;
3. Lumbar spinal stenosis; or
4. Mild hepatomegaly.

[00:41:44]

Faculty Discussion: What are some red flags for diagnosis? What in the history can be helpful?

Now I will ask our faculty, Jill and Gabriel, to chime in here.

So 2 leading questions for this patient. What are some red flags for diagnosis, and what in the history can be particularly helpful for us to pay attention to?

Jill Waldron: Thanks, this is great. It is good to see the results of the polls. I think definitely with his testing you could see that he had the light-chain amyloidosis ruled out and that he had a lot of the risk factors for ATTR cardiomyopathy and for the Val142I. I thought it was interesting that several of you put biopsy vs PYP scan.

Either is okay, either of those answers could be right. The PYP scan is less invasive, so we tend to do that first. And if you do not have a PYP scan at your center, a biopsy is fine. So that is okay too.

I thought it was very interesting that you also put which symptom comes up first, the first-degree AV block, the edema, or the spinal stenosis. So I guess it is technically how you read that. The spinal stenosis obviously probably develops earlier, 5-10 years before, but that is not usually the red flag that we see. Not everybody has edema. Not everybody has heart failure symptoms, although that can be an early sign to clue you in. But really, the AV blocks on the EKG is something that I think sometimes we just skip past, but that is an early sign, and that usually will develop later into a second-degree block or worse. So very interesting to see your responses, but this is a good real case.

Gabriel, what are your thoughts?

Gabriel Dascanio: Yes, I mean, I think it is easy for a lot of us to just dismiss a first-degree AV block, do not worry about it too much, but that starts throwing those red flags when we are talking about amyloidosis. As far as the testing, I would like to add we actually do MRI pretty frequently, and that is also helpful to rule out other causes for that LV hypertrophy and then help solidify that diagnosis for amyloidosis and helping us to avoid having to do more invasive testing like a biopsy.

Jill Waldron: I like that. That is great, and we do the same. And sometimes if we are really not quite sure or they are a little bit younger, we will even do the MRI before jumping to the PYP scan. I did not mention, but if you have parametric mapping on your cardiac MRI these days and you have a native T1 value or the extracellular volume, the ECV measurement is high, I mean, that is what amyloid is, right, extracellular tissue. It is on top of or outside that myocardium. So if you have an ECV greater than 40%, it is 99% sensitive for amyloid, and a T1 mapping greater than, I say 1,000. They usually say 1,025. That is really highly suspicious. And I think a lot of people gloss over T1 mapping because it is parametric mapping because it is newer. You can miss amyloid still if it is not quite in the heart yet on cardiac MRI. It is not perfect, but if you have a significant amount present already in the heart, it is a great tool. I like that.

Dr. Giaconoa: Excellent. Thank you very much both for those insights, and I think we will go ahead and move to our reflection one.

[00:45:54]

So for the audience, we have some polls.

[00:45:57]

Poll 8: How confident are you in your ability to identify early extracardiac red flags (e.g., carpal tunnel syndrome, lumbar spinal stenosis, peripheral neuropathy) that may suggest underlying ATTR-CM?

1. Not confident;
2. Slightly confident;
3. Moderately confident;
4. Confident;
5. Very confident.

[00:46:46]

Poll 9: Take a moment to reflect on what this case brought up for you. What is one area you would like to improve in your diagnosis of patients with ATTR-CM?

1. Recognizing early clinical red flags;
2. Interpreting cardiac imaging findings;
3. Distinguishing ATTR cardiomyopathy from other causes of left ventricular hypertrophy;
4. Integrating multi-system manifestations into diagnostic reasoning; or
5. Communicating diagnostic uncertainty with patients.

So before I move to this next part, I just want to remind you that we have a Q&A at the very end of this session, just like the first 2. So in the Q&A box, please drop in any questions that you have as our presenters are moving through the content so that we can have some discussion at the end that addresses some specific questions that you guys may have.