Activity Transcript

Chapter 1: Can You Tell It's HCM?

Perry Elliott, MBBS, MD, FRCP, FESC, FACC: Welcome to this Medscape educational program looking at the diagnosis and management of hypertrophic cardiomyopathy. My name is Perry Elliott. I'm a professor of cardiovascular medicine at University College in London, and a consultant cardiologist at St. Bartholomew's Hospital.

And what I'd like to do today is to use a case to illustrate some of the signs and symptoms of the disease. This is a 58-year-old male machinist, who whilst continuing to do his physical job, has found over a period of 6 months or more that he now gets breathless on fairly minimal exertion. He's also found that he gets light-headed when running upstairs and when standing quickly and has had 1 near syncopal episode after running. Interestingly, he finds that his symptoms are always much worse after a heavy meal.

There's nothing very significant in his past medical history. He's a nonsmoker and drinks modestly. With regard to his family history, his brother had a history of heart attacks at the age of 40 and 50. Mother died at the age of 92, and his father died from a cerebral hemorrhage at the age of 56.

On examination, he was normotensive. He had a regular pulse, but the pulse character was rapid upstroke and a bisferiens in character. His venous pressure was not elevated. And on palpation of his apex beat, there was a triple impulse that could be felt. On auscultation, he had an ejection systolic murmur at the left sternal edge and a pansystolic murmur at the apex, both of which increased during the Valsalva maneuver and when standing from the squatting position.

Now these physical findings are very suggestive of obstructive hypertrophic cardiomyopathy (oHCM). In this instance, we see evidence for left ventricular hypertrophy (LVH) in the form of the sustained apex beat, and the presence of obstruction results in a jerky carotid pulse, and also an ejection out murmur caused by outflow turbulence, and a pansystolic murmur caused by abnormal anterior motion of the mitral valve (MV). We may also hear in obstructive forms of the disease, a fourth and sometimes a third heart sound.

As part of his routine investigation, he went on to have an electrocardiogram (ECG). This shows an ECG entirely consistent with a diagnosis of HCM, in that it shows LVH, deep S waves in the precordial leads, and also repolarization abnormality with inferolateral T-wave inversion and ST segment depression.

When we now look at his echocardiogram (ECHO), you can see on the left, asymmetric septal hypertrophy, and if you look carefully, you can see that the anterior leaflet of the MV is moving forward systole and making contact with the septum. And you can see this also quite clearly on the M-mode.

If we look at this more closely, we see again the systolic anterior motion of the valve with a color doppler turbulence in the outflow, and a posteriorly directed ejection of mitral regurgitation.

You see the Doppler of the outflow tract, and you see that he had a resting outflow tract gradient of between 2 and 3 m/s, but this is increased significantly during the Valsalva maneuver to almost 4 m/s. So, evidence for provokable left ventricular outflow tract (LVOT) obstruction.

So if we look at this general approach to the diagnosis of HCM, we're using the traditional tools of history taking, physical examination, and the tools that we have available to us every day in the clinic, such as the ECG and the ECHO, to make a fairly firm diagnosis of HCM. Now, in the absence of any other disease features which might suggest some of the rarer causes for this condition, it is then reasonable to consider genetic testing, as at least half of all patients who present with this kind of phenotype will have disease caused by a genetic mutation.

This most commonly occurs in genes encoding the cardiac sarcomeric proteins, and when we perform genetic testing, it's important that before we actually send blood for the test, we counsel the patient on the implications for themselves, as well as their family. Genetic testing may be performed with limited panels, or increasingly through whole-exome screening, and perhaps even whole-genome screening.

In HCM, the main reason to do this test is of course, to confirm the diagnosis, but it's also to help with the evaluation of a family, so that if we identify a pathogenic or likely pathogenic variant, we can then cascade this test to other family members. For those individuals who don't carry the mutation, then in most circumstances, they can be discharged from further follow-up. For those relatives that carry the variant, they require thorough clinical evaluation and long-term follow-up. In individuals who have a classical hypertrophic cardiomyopathy phenotype, and yet we are unable to identify a gene, it remains possible that they still have a genetic form of the condition, and therefore, they may need to remain under clinical surveillance.

So, if we summarize this chapter, I think we can say that many patients with HCM can present with symptoms of fatigue, breathlessness, and chest pain, and sometimes symptomatic arrhythmia.

And that in many cases, this is caused by LVOT obstruction. LVOT obstruction results in characteristic signs and symptoms in the venous pressure, the arterial pulse, in the precordial cardiac impulse, and in the heart sounds. As many patients have familial disease, genetic testing should be considered to confirm the diagnosis and to facilitate the screening of relatives.

I'd like to thank you for listening and for participating in this educational activity.

Chapter 2: Screening to Help Aid With Identification of Hypertrophic Cardiomyopathy

Michelle Michels, MD, PhD: Well, I'd like to welcome you to this chapter on screening to help aid with identification of hypertrophic cardiomyopathy patients. My name is Michelle Michels. I'm a cardiologist based in Rotterdam, the Netherlands, with a special interest in hypertrophic cardiomyopathy.

In taking care of patients with HCM, it's always important to focus on 3 different subjects. First of all, we should try to alleviate the symptoms of the patient. Second of all, sudden cardiac death risk classification is important in every HCM patient, but we should not forget about the family.

Sarcomeric protein gene mutations account for HCM in about half of the patients. These are genes encoding for proteins in the sarcomere, the smallest contractile unit in the heart. In another 5 to 10% of patients with HCM, other genetic and nongenetic causes sometimes presenting with typical extra cardiac features. In about a third of the HCM patients, the etiology is unknown.

Current international guidelines recommend genetic testing in HCM to elucidate a genetic basis and to facilitate the identification of family members at risk. They also encourage you to use genetic testing to identify other genetic causes in patients with atypical presentations, the so-called HCM phenocopies with potential impact on treatment. It's very important that genetic testing should include pre- and posttest counseling. Patients and family members should be informed about risk, the potential harms, and potential benefits of genetic testing. Genetic testing in HCM patients should include genes with strong evidence for HCM.

If genetic testing is performed in patients with HCM, this can lead to 3 different types of results. The most easy part is when we find a clearly pathogenic mutation that is identified as a cause of the HCM, as this enables cascade genetic testing. Family members can undergo presymptomatic testing and can be discharged from cardiac screening in absence of the mutation. Family members that carry the pathogenic mutation require cardiac evaluation and long-term follow-up.

Another possible result is that no mutation is identified. This means genetic testing cannot be used for family screening, and first-degree relatives should be offered cardiac screening instead.

And the most difficult results to get from your genetic testing is that a variant of unknown significant and so-called variant of unknown/uncertain significance (VUS) is found. Clinical screening of family members is indicated. And if other family members with HCM are identified, segregation analysis is possible.

So how does that look like in everyday clinical practice? These are results of our own center in which we screened 209 probands, and the majority of them underwent genetic testing. So, in 94% of patients, genetic testing was done, and in this cohort with a really strong family history of HCM, we found pathogenic mutations in the vast majority.

This led to 777 relatives that were screened, and 80% of them underwent genetic testing. Fifty-seven percent of those who underwent presymptomatic genetic testing were actually genotype negative. And these patients, these family members could be reassured and did not need cardiac screening. Forty-three percent of patients or family members were genotype positive, and they were referred to cardiac screening, as were the 20% of family members in which genetic testing was not performed. What we did see at cardiac screening, including ECG and ECHO, we found HCM in 37% of patients, of family members that were actually genotype positive, but we also found HCM in 28 family members without genetic testing. So, this led to 17% of total. So cardiac screening in family members requires serial assessments, including ECG and cardiac imaging, and it's recommended at periodic intervals, suggesting timing and intervals differ between guidelines. In general, shorter time intervals are recommended for kids and longer intervals for adults.

So, what are the conditions for genetic assessment of HCM? Well, I believe that this should ideally be performed in specialized multidisciplinary HCM centers. The multidisciplinary team consists of dedicated imaging cardiologist, clinical geneticist, molecular geneticist, and allied professionals, and sometimes also a radiologist can be added to this team. Counseling to inform about the potential benefits and potential harm like psychosocial, ethical and insurability is especially important in presymptomatic testing of family members. Interpretation of genetic test results is done by the molecular geneticist and this means the determination of pathogenicity of variants. And every HCM center should have regular multidisciplinary team meetings to discuss individual cases, including reevaluation of phenotyping, genotyping, and family history.

So, to summarize, I'd like to say that genetic testing in HCM is recommended by international guidelines. Counseling should be an integral part of genetic testing, pretest counseling, but also posttest counseling. Multidisciplinary teams are necessary to interpret results from both clinical and genetic testing. Genetic testing in HCM can lead to identification of family members at risk. And in specific cases, genetic test results may alter the clinical management.

I'd like to thank you for participating in this activity.

Chapter 3: How Can We Utilize Echocardiography For Diagnosis?

Theodore P. Abraham, MD, FACC: Welcome to this Medscape session on how to utilize echocardiography for the diagnosis and management of hypertrophic cardiomyopathy. My name is Ted Abraham. I'm the Meyer Friedman distinguished professor of medicine at University of California in San Francisco.

Hypertrophic cardiomyopathy, as we all know, is the most common inherited heart disease, and I would say it is a disease of imaging. Multimodality imaging is used to characterize HCM and to allow us to better evaluate a patient with regards to diagnosis, management, monitoring, and monitoring after therapy. However, echocardiography (ECHO) the is the keystone of all these decisions. Both ECHO and advanced ECHO, including transesophageal echocardiography (TEE), encompass every single step of the management of an HCM patient.

The key diagnosis of HCM needs ECHO. The key features are septal hypertrophy of at least 15 mm or more that is usually diagnosed with ECHO. Other features commonly seen are systolic anterior motion of mitral valve and left ventricular outflow tract gradient. ECHO is also used to classify patients into the 3 categories of HCM patients based on gradient. If they have a gradient < 30 mmHg at rest and with provocation, that is nonobstructive. If their gradient is > 30 mm Hg at rest and with exercise, that is obstructive HCM. And if the gradient is < 30 mmHg with rest but > 30 mmHg with provocation, that would be latent or labile obstructive HCM.

Once the decision is made, the patient is followed using gradients, especially in the obstructive variety, under medical therapy and additional imaging. Often, TEE is used to determine their suitability for either septal ablation or septal myectomy. Very often in high-quality cases, this can be done even with a standard ECHO. The use of contrast has increased substantially in HCM. This is whether it is to confirm the phenotype, confirm what the septal thickness truly is, or to assess the apex. We now know that there is many midventricular and apical varieties of HCM that are best assessed with contrast ECHO. Lastly, ECHO is used intraoperatively both with septal ablation and with septal myectomy. In septal ablation, it is used to, 1, identify the point of maximum septal-systolic anterior motion (septal-SAM) contact, which is the point of the dynamic obstruction. Once the septal perforator is engaged, when contrast is delivered, we use ECHO to confirm that the contrast is actually ending up in the right location, which would then predict a high rate of success of a septal ablation. And lastly, in the catheter laboratory, it is used to determine both preablative gradients and postablation gradients.

In the case of septal myectomy, use of both standard transthoracic ECHO and TEE are important. Here, TEE helps plan for surgery and intraoperatively allows the surgeon to reassess the situation prior to myectomy and immediately postmyectomy as soon as they come off bypass to make sure that all the key anatomic features have been addressed and that truly the gradients are now in a normal range. This could be challenging given the changing, shifting hemodynamic situation and the immediate postbypass condition. However, most times, if the anatomy and physiology look good, this is a predictor of success. Lastly, HCM can be risk assessed using multiple imaging modalities, again, starting with ECHO. If the septal wall thickness is > 3 cm, that often portends higher risk for sudden cardiac death. That, along with other indicators, such as magnetic resonance imaging (MRI), whether it is wall thickness or extent of scar, typically > 15% would portend high risk for sudden cardiac death.

My concluding comment would be the use of novel imaging methodologies relating to ECHO, in particular cardiac mechanics. We use strain derived from ECHO. Now it is typically 2-dimensional or speckle tracking strain, and global strain happens to be a good indicator of survival. Strain is often reduced in hypertrophied parts of the heart, and if global strain is < 10, both our data and multiple other investigators have shown that this portends a very poor prognosis. I want to add here that ECHO is also useful to diagnose patients who have transformed from a hyperdynamic or a normal ejection fraction heart to the classic low-ejection fraction heart failure, or the so-called burnt-out variety or end-stage HCM. This is important because, 1, this portends a poor prognosis, number 2, it indicates the need for a change in strategy. Most of these patients might end up needing guideline-directed medical therapy under heart failure guidelines, they may need referral to a heart failure specialist, and they may need evaluation for advanced heart failure therapies, including heart transplant.

In conclusion, HCM is a disease of imaging. And among multiple imaging modalities, ECHO, including TEE, are the keystones of both diagnosis, determination of management, and monitoring of therapy in patients with hypertrophic cardiomyopathy.

Thank you.

Chapter 4: Differential Diagnosis: Diseases With Similarity to HCM

Perry Elliott, MBBS, MD, FRCP, FESC, FACC: Welcome to this Medscape Educational Activity. My name is Perry Elliott. I'm a professor of Cardiovascular Medicine at University College in London and a consultant cardiologist at St. Bartholomew's Hospital. In this chapter, we're going to be considering the differential diagnosis of HCM.

Now, cardiomyopathies are defined by the structure and function of the left and the right ventricle. In the case of hypertrophic cardiomyopathy, the disease is very simply defined by the presence of increased left ventricular wall thickening that is not solely explained by abnormal loading conditions such as valve disease or hypertension. This means in an adult, a wall thickness in any segment of > 15 mm is usually sufficient to make the diagnosis, and in a child a wall thickness > 2 SDs above the predicted for the child's age.

Now, in the majority of cases, HCM is caused by mutations in the genes that encode cardiac sarcomeric proteins. There also may be between 10 and 15% of patients who have disease caused by other rare so-called phenocopies, some of which are genetic and others which are acquired. The approach to diagnosis should always begin with a good family history, physical examination and history taking, and then the usual tests that you have available to you in the clinic, the electrocardiogram and cardiac imaging.

In this process, we should be looking for features from the history or from the tests that we do that suggest a patient may have one of the rarer phenocopies for the disease. Now, this doesn't have to be very technical. It can be something as simple as the age of the patient, because the differential diagnosis of HCM varies according to the age group. In the older patient, for example, you might have to consider diseases such as amyloidosis. In a child in the first year of life, then you may consider inherited metabolic disorders.

The age of the patient and of course their family history, the pattern of inheritance, and also the presence of noncardiac signs or symptoms. Perhaps one of the more common of these is carpal tunnel syndrome, which if bilateral may suggest a diagnosis of amyloidosis in an older patient with concentric left ventricular hypertrophy (LVH).

If we look at the electrocardiogram, again, there may be some diagnostic red flags that we can utilize in directing our diagnostic pathway. If a patient, for example, has relatively small-voltage ECG, in spite of the presence of severe thickening on their ECHO or MRI, we may need to think about amyloidosis. If the patient has a short PR interval without preexcitation, this is something we sometimes see in people with Fabry disease, and with preexcitation is a feature of some storage diseases such as glycogen storage disease, Danon’s disease. When we look at imaging in HCM, there are very few images which are pathognomonic for particular disease subtypes, but if we interpret the images in context, it can be helpful. On this slide, on the right-hand side, you see a patient who has concentric LVH and on the ECHO has a reduction in longitudinal strain in the posterolateral segment. This corresponds with a scar, and in this context in a middle-aged patient, this is something that we may see in patients with fibrous disease.

An example of an imaging appearance which can be fairly specific is shown here. On the left, we have an MRI still showing us concentric LVH. In the center, we see the gadolinium-enhanced image which shows diffuse uptake of gadolinium, and this is highly suggestive in the right context of cardiac amyloidosis. It doesn't tell us the type of amyloidosis, however, and this may require further testing. For example, what you see on the right is a bone scan, bone scintigraphy, showing uptake in a patient with transthyretin amyloidosis.

Moving to laboratory tests, there are a number of tests that we can perform that tell us about the severity of the condition, such as internal pro b-type natriuretic peptide (proBNP) or troponin T. But there are a number of routine tests that can help us, again, in identifying some of these rarer phenocopies. For example, a patient with a raised creatine phosphokinase may have an underlying metabolic disorder such as Danon's disease or mitochondrial disease. Patients that have abnormal renal function, we should also be thinking there about amyloidosis, Fabry disease, and some mitochondrial disorders. There are also tests that we should be considering perhaps in the majority of patients who present with LVH, as these may be the only clue to the underlying phenocopy. The 2 examples I've shown on this slide are the measurement of ɑ-galactosidase to detect Fabry disease and also the exclusion of a plasma cell dyscrasia in patients with possible amyloid light-chain (AL) amyloidosis.

To summarize, when we are approaching a patient with HCM, before we embark on highly specialized tests, we can use the history, the physical examination, and the routine tests of ECG, ECHO, and cardiac imaging to give us some clues to the presence of some of these rarer genetic and acquired phenocopies. The key learning points here, I think, is that the term HCM describes a family of genetic and acquired disorders; the majority are genetic in origin; and that rare phenocopies should be considered in all patients with these so-called diagnostic red flags.

Thank you for participating in this activity.

Chapter 5: Steps Toward a Multidisciplinary Referral of HCM

Theodore P. Abraham, MD, FACC: Welcome to this Medscape seminar on "Steps Toward a Multidisciplinary Referral of Hypertrophic Cardiomyopathy." I am Ted Abraham, Meyer Friedman distinguished professor of medicine at University of California in San Francisco. And it is my pleasure to welcome today Dr Michelle Michels from the Thoraxcenter, Erasmus University in Rotterdam, Netherlands. Welcome, Dr Michels.

Michelle Michels, MD, PhD: Thank you.

Dr Abraham: Hypertrophic cardiomyopathy often is thought to leverage multimodality imaging, but in truth, it really leverages a multispecialty care, and it involves multiple specialties within cardiology and sometimes outside of cardiology that need to come together to offer the optimal and best care and management of a patient and family with hypertrophic cardiomyopathy. So, on that note, I'd love to ask Dr Michels, how are you in your practice and in Europe using the multispecialty approach to HCM care?

Dr Michels: So, well, we currently still use the 2014 European Society of Cardiology (ESC) Guidelines on the Diagnosis and Management of HCM. They already give the advice to really use a multidisciplinary approach. The first clinical evaluation of a patient with HCM should include at least a pedigree, the signs and symptoms of a patient, the electrocardiogram, cardiac imaging, including both echocardiogram and cardiac magnetic resonance imaging (CMRI), if available, and some laboratory tests. And then the guidelines also advise to refer patient to multidisciplinary specialist teams in case there is an uncertain diagnosis, but also if patients have severe symptoms of increased risk for disease-related complications, like sudden cardiac death. But also, for genetic counseling and testing, especially for invasive therapies like septal reduction therapy. So, if you take all these reasons for referral into account, I do believe that actually the guidelines are saying that we should at least refer every patient with HCM once to a specialist team in order to get all the different aspects of this disease accounted for. And I would be very nice to know what is the current practice in the United States?

Dr Abraham: Thank you, Dr Michels. And I would say that our practice is very similar to what you described as whatever you're doing in Europe and in your center. As you know, we follow mostly our 2020 American Heart Association/American College of Cardiology Guidelines. And they say that the primary cardiologist might be useful in evaluating and making the initial diagnosis of hypertrophic cardiomyopathy, but that it is important for a multispecialty center of excellence or a specialized center in HCM to make more-nuanced decisions. And that a multispecialty approach to their care would be important in optimizing care for an HCM patient and their family.

So, similar to you, important decisions on genotyping involving genetics and genetic counseling. Phenotyping, especially when sophisticated measures of imaging are utilized, like MRI or positron emission tomography (PET) scanning. And lastly, when decisions are being made for nonmedical therapy, septal reduction therapy that you alluded to. Or more importantly, when non-core HCM clinicians have to be involved, whether it's implantation of an implantable cardioverter-defibrillator (ICD) for patients that have heart failure symptoms, whether they need to. . . . Especially if they have low ejection fraction go into a realm of guideline-directed medical therapy or, in the rare case, be leveraged and evaluated for a heart transplant. All those are best done within a multispecialty unit of care or team of care. We also implement a shared decision-making model, where the patient along with multiple care providers make decisions together and hopefully take the patient on a more useful patient journey through HCM.

So, getting kicking the ball back to you now. Where do you think are some critical steps in this transition from a primary care to the specialty care, and where in your mind do you think are some of the critical decision-making points within a multispecialty team?

Dr Michels: In my own practice, I actually do prefer to get the patient in quite early, so early after diagnosis. And then we can take a closer look at the phenotyping and also introduce genotyping in the patient. Risk stratification and phenotyping [are] actually improving in patients that are referred to HCM centers. And I think, it's really crucial for invasive therapies as we know by literature, there's a clear association between postural volume and complications. And I think we also should take into the account, the introduction of new pharmacological options that come available for HCM. So, I think these are good reasons to refer a patient. And also the shared decision-making that you mentioned is extremely important in HCM. We should really guide our patients through their life, give their lifestyle advice on exercise, give some family advice, provide genetic counseling. So, I think these are all reasons why it's good that every HCM patient should at least be seen once in a HCM center of expertise.

Dr Abraham: Thank you. And I think we agreed on not delaying the diagnosis, that patients who are diagnosed at a primary cardiology level should be quickly transitioned to a center of excellence. That this multispecialty center should have specialists with expertise and experience with HCM and may involve multiple specialties, HCM clinical care, imaging, electrophysiology, genetics, heart failure, and maybe many more. I like that you brought up the issue of lifestyle. Many of our patients, as you know, are young, active, and we need to counsel them on lifestyle. And lastly, that we envelop all this in a model of shared decision-making, where the patient is an important component of the decisions we are making about their lives. And I think taking this approach early and consistently throughout their patient life journey would offer a very optimal care for a patient with HCM.

It was a pleasure to be with you, Dr Michels. Thank you.

Dr Michels: Thank you.

This is a verbatim transcript and has not been copyedited.