Hypertrophic cardiomyopathy making the diagnosis.

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In this slide, you can see a nice summary of hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is defined by an increased left ventricular wall thickness equal or exceeding 15 millimeters. In the left upper panel, you can see the typical echocardiography image of a patient with hypertrophic obstructive cardiomyopathy with asymmetrical hypertrophy systolic anterior motion of the mitral valve, and this is a patient with obstruction.

Half of the patients with hypertrophic cardiomyopathy don't have any complaints, patients that do have complaints often complain about shortness of breath, syncope, pre-syncope, and heart failure symptoms. We are of course afraid of sudden cardiac death, especially during exercise. The pathological hallmark of hypertrophic cardiomyopathy is depicted in a right upper panel where you can see the myocardial disarray. Below that, you can see a typical CMR image of a patient with hypertrophic cardiomyopathy with late gadolinium enhancements depicting replacement fibrosis. We do have treatment options for patients with hypertrophic obstructive cardiomyopathy, like the myectomy and an alcohol septum ablation in the lower panel, and we can prevent sudden cardiac death by the implantation of ICDs. Hypertrophic cardiomyopathy is often a familiar disease with an autosomal dominant pattern of inheritance, which means you also have to take attention and care about the family members, and in patients with genetic hypertrophic cardiomyopathy, pathogenic DNA variants and sarcomere genes are present.

If we'd like to make the diagnosis in hypertrophic cardiomyopathy, we should identify patients with cardiac hypertrophy, and this starts with an index of suspicion. Of course, the patient can have symptoms like shortness of breath, chest pain, palpitations, pre-syncope, or syncope, but we often get patients referred with just an abnormal ECG without complaints or cardiac murmur. Of course, we have patients that come from a family of unknown hypertrophic cardiomyopathy and especially in first-degree relatives you should have a high index of suspicion. If you are making the diagnosis of hypertrophic cardiomyopathy, clinical assessment is focused on etiology, including genetic testing, pathophysiology, treatment options, and recertification for sudden cardiac death. The etiology of hypertrophic cardiomyopathy, in almost half of the patients a pathogenic DNA variant in the sarcoma protein gene is involved, and especially myosin binding protein C3, and myosin heavy chain are involved in hypertrophic cardiomyopathy. In almost a third of the patients, we have unknown etiology, and of course, there are also other genetic and non-genetic causes like cardiac amyloid Fabry or Denon disease, which we should call hypertrophic cardiomyopathy, phenocopies. It's really important in making the diagnosis that we also have some information about etiology, especially with new treatments entering the field.

This clinical evaluation of a patient with left ventricular hypertrophy, it's crucial to pay attention to the family history. Just draw a little pedigree signs, of course, symptoms, the ECG, cardiac imaging, and some really routine laboratory test. If you have features of a specific disease, you can either really go in that direction, or ask for specific genetic testing. If you don't have any clue which specific disease is underlying this left ventricular hypertrophy, then we continue with genetic testing. In history and physical examination, it's important to pay attention on the age and the gender of your patients as most inherited diseases occur in younger patients, and most left ventricular hypertrophy caused by hypertension, or cardiac amyloid will happen in older patients. Gender, you should also take into account gender in hypertrophic cardiomyopathy. Race ethnicity is also important, especially in inherited TTR cardiac amyloids, there's a high prevalence of pathogenic DNA variants in Blacks. You should pay attention to extracardiac manifestations like carpal tunnel in cardiac amyloid and also pay attention in the mode of inheritance, for example, mitochondrial diseases are inherited in a X-linked pattern.

The ECG is often overlooked but it's really important in hypertrophic cardiomyopathy as first of all it could raise the suspicion of hypertrophic cardiomyopathy if you see left ventricular hypertrophy on the ECG, but also, ECGs abnormalities may suggest a specific diagnosis or morphological variants like giant negative T wave inversion that can be present in a patient with apical hypertrophic cardiomyopathy, low or normal QRS voltages in the presence of left ventricular hypertrophy should point to the direction of cardiac amyloids, pre-excitation in a patient with storage diseases like Pompe, Danon, or PRKAG2 and abnormal Q waves can point in asymmetrical left ventricular hypertrophy or replacement fibrosis.

In this slide, you see some examples of ECGs of patients with left ventricular hypertrophy. Then in the lower part, this is a patient with apical hypertrophy, and actually, his first echo came back normal but that was because they didn't pay attention to the apex of the heart. In the upper right panel, you can see a patient with Danon disease, extensive left ventricular hypertrophy with regularization abnormalities, but also a really short PR interval and pre-excitation. Then in the lower panel on the right, this is a patient with cardiac amyloid with extensive hypertrophy on echo but you see actually normal voltages or even lower voltages and also the presence of pathological Q waves. This is a patient with cardiac amyloid. Then echo, echocardiography in cardiology, in general, is central in making the diagnosis and also monitoring of hypertrophic cardiomyopathy. It can give us a really good impression of the left ventricular wall thickness, but also the systolic function, diastolic function, left atrial enlargement, mitral valve abnormalities, and of course, if we're talking about left ventricular hypertrophic obstructive cardiomyopathy also in the left ventricular outflow tract obstruction both in rest and during provocation. Left ventricular outflow tract obstruction is a typical hallmark of hypertrophic cardiomyopathy and you should really look for it so you should make echo images both in rest and during physiological provocation with Valsalva or exercise and a definition of left ventricular gradient obstruction is equal or exceeding 30 mm of mercury. If it's above 50, it's hemodynamically important and might point in a specific treatment option.

Then a word on cardiovascular magnetic resonance imaging. It can show us many of the things that echo can also do, but I think it's really important for myocardial tissue characterization and also plays an important role in patients with less optimal echo images. Patients with poor echo windows or echocardiography inconclusive, suspicion of an alternative diagnosis, but also, for risk stratification, the maximum wall thickness, ejection fraction, presence of apical aneurysms, and extended fibrosis. It can also help us to guide our invasive therapy, especially on mitral valve abnormalities, papilloma muscle abnormalities. These are some clinical images of patients with hypertrophic cardiomyopathy from our own clinic. On the left side, you see a patient with an extensive apical aneurysm which is really nicely shown by their CMR. In the middle panel, this is a patient with hypertrophic cardiomyopathy carrying a myosin heavy chain mutation, you can see the extensive late gadolinium enhancement. On the right part, you can see the typical image of late gadolinium enhancement in cardiac amyloid pointing in another direction, then classical hypertrophic cardiomyopathy.

To conclude, I think it's important that we all have an index of suspicion of hypertrophic cardiomyopathy in patients that we are encountering. We start with a classical clinical evaluation including cardiac images with a special focus on both history of the patient for extracardiac manifestations, but also the family history. Don't forget about the ECG. I think there's a central role for echo including provocation of left ventricular outflow tract obstruction. CMR really has an added value in hypertrophic cardiomyopathy, and I think it should be performed in any patient presenting with left ventricular hypertrophy. I'd really like to thank you for your attention.

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