Ladies and gentlemen, my task today is to review with you the problem of diagnosing hypertrophic cardiomyopathy. What a cardiologist needs to know, it looks very simple because hypertrophic cardiomyopathy is defined by a presence of increased left ventricular wall thickness in whatever segment you choose and wherever it's possible to measure it over 15 millimeters. This seems very simple, and diagnosing hypertrophic cardiomyopathy can stop here, but we know that this is not it, and there are many processes that should follow. We should keep in mind that 15 millimeters is an arbitrary value, that it could be different for different conditions. For example, in relatives with hypertrophic cardiomyopathy patients in their families, it should be more than 13 millimeters. Also, some metabolic cardiomyopathies and other hereditary conditions can give you less hypertrophy, and they already can qualify as hypertrophic cardiomyopathy. It's also not that simple in children when we are using, especially for the younger ones, the average, the median values for the population, and we are calculating standard deviations, so-called z-scores, and then we are able to diagnose hypertrophic cardiomyopathy.
We should keep in mind that diagnosing hypertrophic cardiomyopathy based on hypertrophy is not the same thing as clinical hypertrophic cardiomyopathy. We can appreciate that by comparing the prevalence of hypertrophic cardiomyopathy, in a study where echo was used, for example, in the CARDIA study where the prevalence was very high. It was almost 1 in 500. As compared to that, for example, insurance claims in Germany are showing that the prevalence is way lower, two to three times lower. If I can make a reference to our own population in the Czech Republic, it's about 10 times lower. Hypertrophic cardiomyopathy is an underdiagnosed condition.
I would like to bring your attention to a cardiomyopathy mindset, which was proposed by the working group on myocardial and pericardial diseases, and particularly by Claudio Rapezzi.
He suggested that we shouldn't start just simply by doing ECG and echocardiography or even more advanced cardiac magnetic resonance imaging and measure the thickness. We should keep in mind that cardiomyopathy is very often a genetic disease, and we should take personal history of the patient and family history of the patient, and the personal history can show you the severity of the disease. Of course, the symptoms, the degree of symptoms is important, but also it can show you involvement of other organs. Many cardiomyopathies are falling in a tableau of a complex syndrome, and family history is important because there could be other subjects that are affected by cardiomyopathy, not just the proband. The family screening should follow. We shouldn't forget about family members that can also bear this condition. Biochemistry is important because we can not only appreciate the severity of the disease by measuring, for example, troponin and NT-proBNP but also appreciate involvement of other organs, which may again suggest that this is a syndrome and not just simple hypertrophic cardiomyopathy involving the heart. Then genetics. Genetics seems to be a very simple solution, but I'll show you that this is not the case, and it could be very complex, so endomyocardial biopsy may be the ultimate solution to make the diagnosis. You can see that this is a complex process, but let's take it from the beginning.
Let's take the patient who is coming to us, either with symptoms like heart failure, arrhythmias, or an asymptomatic subject who was diagnosed during a screening, for example, an athlete with a cardiac hypertrophy that's not appropriate to the exercise he's doing, or hypertrophy cardiomyopathy is in the family.
Then the trajectory starts with diagnosing hypertrophy. Hypertrophy, of course, is diagnosed by imaging, but we shouldn't forget about ECG. ECG is very simple. We do it at the beginning. Here you can see the simple hypertrophy, no major repolarization changes. This is a genetically tested negative patient. There could be more complex pictures like this one. This is beta myosin heavy chain patient, on top, carrying also a variant associated with Brugada syndrome. There could be some very suggestive electrocardiograms, for example, like this one. This is a Fabry patient, and you can see the short PR, the right bundle branch block, enormous repolarization changes, tall voltages, or even more suggestive like this one where you can see the pre-excitation, the short PR, and this is Danon disease. ECG can be very helpful already in making differential diagnoses.
Then we are, of course, moving to imaging and we are starting with echocardiography. I would like to remind us that the measurement of the thickness should be done in all possible visualized segments and that's quite important. Sometimes echo is not good enough and sometimes we are not able to see properly, so cardiac magnetic resonance is much better to measure the thickness, but the thickness is only part of the picture and it can go much, much further. Already, we can, from the picture, suggest that there might be other sources causing hypertrophic cardiomyopathy than the sarcomeric mutation like this homogeneous, enormous hypertrophy where you can suspect a metabolic disease or mitochondrial disease, so echocardiography and cardiac magnetic resonance structural imaging is very important.
On top comes obstruction. Obstructive cardiomyopathy is a major issue. Here, you can see the typical cause of left ventricular obstruction in the outflow tract where you can see the SAM, the systolic anterior movement, of the mitral leaflet causing a gradient in the outflow tract.
You can enhance it, for example, by using Valsalva maneuver. Valsalva maneuver is not very well standardized. We are still using it. It's very helpful, but you can put your patient in the upright position, in the sitting position, or even better, you can exercise the patient. Here, you can see a subject with minimal gradient at rest where we were able to provoke a significant obstructive gradient by exercising the patient on this special bike, up to 100 watts, which is not a major load, but it can already provoke a significant gradient. If you are thinking about a population of patients with hypertrophic cardiomyopathy, about one third have an obstruction at rest, but another third may have it provoked by exercise.
Another important feature not to forget is that obstruction may be associated with mitral valve disease, with mitral regurgitation. This may lead to some errors in measurement. We can mistake the obstructive gradient with the flow of mitral regurgitation, but in particular, we should consider that when referring patients to septal reduction therapies.
Now, we are coming to differential diagnosis, and that's an important part of our task. At least, we have to evaluate the patient as internists. We have to look on other systems like central nervous system, like muscle system. Cutaneous changes should be explored, renal involvement. It all may be suggestive of complex syndromes. For example, like amyloidosis, like mitochondrial disease. Friedreich's ataxia comes to that. A lot of them are associated with multisystemic appearance and other organ damages.
With this, we are very much helped by laboratory findings. Of course, as cardiologists, we are operating very frequently with natriuretic peptides and troponins. Those are important because they are associated with increased severity of the disease, but then we have to seek other features of syndromes, for example, muscle damage, which is suggested by elevated CPK, or lactate comes to that, or myoglobinuria. Of course, those syndromes may affect other organs like kidneys, so serum creatinine, proteinuria. Sometimes we are using specific diagnostic tests. For example, enzymatic activity in lysosomal storage disease. Specific markers are also associated with lysosomal storage disease. Again, albuminuria, when it's present, we should see for the M-protein by immunofixation, and we should assess the serum-free light chain ratio to exclude AL amyloidosis.
Imaging is also very helpful and magnetic resonance, with its capacity to do the tissue characterization, is of enormous help in making differential diagnoses. Again, I would like to bring up amyloidosis as a potential diagnostic issue in magnetic resonance where you can see the subendocardial late enhancement, difficult nulling, or Fabry disease, which is associated with the posterolateral storage and fibrosis. Here, we can see changes on MRI that are suggestive of different types of involvement, but MRI is way more complex now. T1 mapping and T2 mapping is helping us in making differential diagnosis.
Again, making reference to amyloidosis, you can see that we are starting with echo. Echo may already suggest the presence of amyloidosis, thickened valves, thickened interatrial septum, apical sparing, then MRI. Then we are getting to special techniques and we are using bone scintigraphy which is suggestive of the presence of TTR amyloidosis, but this should be done together in association with biochemical testing to exclude AL amyloidosis by the presence of M spike on immunofixation and aberrant serum-free light chain ratio.
Now, biopsy, is it dead? Is it not needed in hypertrophic cardiomyopathy? This is a position statement, which was done by a joint activity across the globe, actually, and there are still situations where endomyocardial biopsy can be very helpful.
Of course, myocarditis is one of the situations, but also other cardiomyopathies that are not clearly diagnosed. By genetic testing, by imaging, like for example, mitochondrial cardiomyopathy and some storage diseases.
Now, genetic testing, it seems to be the ultimate solution, but before doing that, we need to try to establish the inheritance pattern, which is typically associated with hypertrophic cardiomyopathy, that autosomal dominant for sarcomeric cardiomyopathies, but again, there are conditions, the phenocopies of hypertrophic cardiomyopathy, that have a particular association or particular inheritance pattern. For example, X-linked Fabry and Danon disease or matrilinear in mitochondrial DNA mutations.
Again, a position statement by the working group of myocardial and pericardial diseases was suggesting that we should aim to make it as a clinical diagnosis, so we should use panels of genes that are known to be associated with hypertrophic cardiomyopathy, but you can do broader and broader spectrum of genetic testing. Not only sarcomeric genes, or sarcomeric proteins, genes that are associated with hypertrophic cardiomyopathy and well-established, but then you may be facing a very complex problem.
If you are finding a pathogenic mutation, if you are on the right side of this triangle, it's very simple and it looks very straightforward, but unfortunately, it's not the case in many patients. In many patients, we are having either likely probably pathogenic variants or even worse variants of unknown significance or benign variants. So, the association, the segregation with cardiomyopathy in the family, and the search of the literature, and also sharing the data is important, and consultation with clinical geneticists is very, very important to establish pathogenicity, and not to bring a burden on the family by telling them you have a variant that's causing the cardiomyopathy, which is then revealed to be benign after several years of the follow up of those patients. Genetics are important, but not all patients are having a variant and many of those having a variant are not having a pathogenic one.
Last but not least, diagnosis is helping us to make the assessment of risk. I was mentioning already biomarkers, NT-proBNP, high sensitivity troponin, and you can see here on high sensitivity troponin T, it's associated with worse prognosis and so is elevation of NT-proBNP, but most of us are thinking about the risk of sudden cardiac death.
Here we are very much assisted by cardiac imaging. Measuring the thickness, assessment of obstruction, dilatation of left atrium, those are parameters associated with increased risk, but on top it comes that the presence of apical aneurysm is a risk factor. Extensive fibrosis, especially exceeding 15% of left ventricular mass is associated with worse prognosis and development of so-called burnt-out hypertrophic cardiomyopathy with dilatation and dysfunction of left ventricle. This is also a significant risk factor, but still the appreciation of the risk is based on that one we were proposing in 2014 in the guidelines but on top, we are now considering those additional risk factors. In the new guidelines that we are just issued, you will learn about it, and it brings us a bit closer to the overseas guidelines that we're already suggesting that in the past using more complex algorithm for the assessment of the risk of sudden cardiac death. We are still using validated algorithm for the risk assessment, but on top of it, we should consider additional factors whenever the patient is in the gray zone where we are deciding whether to put an ICD or not.
Let me conclude that the patient's trajectory in cardiology practice is not just about making the diagnosis by measuring the thickness. It's way more complex. We have to assist left ventricular obstruction tract. This is guiding the therapy and this is also deciding on the patient's trajectory afterwards. The differential diagnosis is important. Some of those cardiomyopathies are now having specific treatments and this should be also taken into account. For the family, it's important to have the genetic testing and the cascade family testing because they may be either excluded from the follow-up or included in the dispenserization and follow-up for the future. Last but not least, we have to re-assess the risk of patients, their prognosis, their risk of sudden cardiac death, and this is a decision-making process in a way to implant an ICD. With this, I would like to conclude and thank you for your kind attention.
