Show notes
CardioNerds Rounds Co-Chair, Dr. Karan Desai, joins Dr. Michelle Kittleson (Director of Postgraduate Education in Heart Failure and Transplantation, Director of Heart Failure Research, and Professor of Medicine at the Smidt Heart Institute at Cedars-Sinai) to discuss challenging cases of hypertrophic cardiomyopathy. As a guideline author on the 2020 ACC/AHA Hypertrophic Cardiomyopathy Guidelines, Dr. Kittleson shows us how the latest evidence informs our management of HCM patients, while sharing many #Kittlesonrules and pearls on clinical care. Come round with us today by listening to the episodes now and joining future sessions of #CardsRounds!
This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.
Speaker disclosures: None
Cases discussed and Show Notes • References • Production Team
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Show notes - Hypertrophic Cardiomyopaty Cases
Case #1 Synopsis:
Two non-white brothers in their early 20s come to clinic to establish care. They have no cardiopulmonary symptoms, normal EKGs and normal echos, but there was a possible family history of HCM. Their mother had LV hypertrophy and underwent septal myectomy, but she could not afford genetic testing and was no longer in the patients’ lives. The path report suggested “myocyte hypertrophy without disarray or bundles of myocytes.” How would you advise these patients regarding screening and surveillance? Listen to #CardsRounds for the full details!
Quotes from Case #1:
“Let’s take a walk down memory lane and let’s get to our evolution of understanding hypertrophic cardiomyopathy… [our understanding] follows the parable of the six blind men and the elephant. Each of the six blind man approached it from different angles, its tusk, its ear, its tail, and they all try to convince each other what an elephant is … because none of them can see the big picture.”
Dr. Kittleson on the history of HCM and coming to a unifying diagnosis
“The next time you are sitting there mashing your teeth because you have to memorize what the HCM murmur does squat to stand, Valsalva, or handgrip … remember you are standing on the shoulder of Giants. They [Drs. Braunwald and Morrow] pioneered surgical myectomy based on physical exam and cath lab findings”
Dr. Kittleson on the physical exam guiding HCM management
Takeaways from Case #1
Before we round, we think it is important to get on the same page regarding the nomenclature around HCM.
Since the original characterization of hypertrophic cardiomyopathy (HCM) more than 60 years ago (see the Braunwald Chronicles for the origin stories!), different terms have been used to describe the disease. These include idiopathic hypertrophic subaortic stenosis, hypertrophic obstructive cardiomyopathy (HoCM), and “burnt out HCM” when heart failure develops.The 2020 guideline committee recommended a common language to avoid confusion: since left ventricular (LV) outflow tract obstruction (LVOTO) occurs in 60% of patients over time, but one-third remain non-obstructive, the recommendation is t0 call the disease state HCM with or without outflow tract obstruction.Dr. Kittleson added that when heart failure develops we should characterize the pathology as HCM with heart failure rather than “burnt out HCM.”
Do we use HCM to describe any LV that has thick walls?
Some clinicians will use HCM to describe all disease states that can lead to increased LV wall thickness, including those associated with systemic disorders such as RASopathies, mitochondrial myopathies, glycogen/lysosomal storage diseases, Fabry’s disease, hemochromatosis, Danon disease, and amyloidosis (especially in adults).However, the pathophysiologic mechanisms, genetic underpinnings, and treatment of these diseases are different. Secondary causes of left ventricular hypertrophy (LVH) – such as athlete’s heart and hypertensive disorders – can also cause confusion with identifying the correct terminology and diagnosis.As Dr. Kittleson (and the guidelines) made clear, the clinical definition of HCM is a disease state in which (1) the morphologic expression is restricted to the heart, characterized primarily by LVH in the absence of another systemic; (2) a metabolic or cardiac cause; (3) and for which a disease-causing sarcomere (or sarcomere-related) variant is identified or genetic etiology remains undetermined.See some of our original CardioNerds episodes to review the clinical manifestations, diagnosis and treatment of HCM!
Ok. We are with you on the terminology! But as you mentioned there are many disease states that can look like HCM. What are phenocopies?
As alluded to above, there are multiple genes that can lead to the phenotypic appearance of HCM, but rather these are “phenocopies” masquerading as HCM.Dr. Kittleson noted that many of these phenocopies are diagnosed in childhood (e.g., glycogen storage diseases, Friedrich ataxia, Danon disease); however, for adult cardiologists, particular attention should be given to recognizing amyloidosis (see our Amyloidosis page).We should remain alert for “LVH+” states: when we see left ventricular hypertrophy but also systemic signs including peripheral neuropathy, renal dysfunction, and skin changes, which could clue us into a systemic pathology like Amyloidosis. After all, Imitation is the sincerest form of flattery!The classic pathologic findings of HCM include myocyte disarray (where individual cardiomyocytes vary in size, shape and form), abnormal intercellular connections, expansion of the interstitial compartment and areas of replacement fibrosis, and small vessel disease (in which intramural vessels are narrowed by medial hypertrophy).
So back to this case. It is possible the patients’ mother had a HCM phenocopy. And the pathology was not classic for HCM. What do the guidelines say regarding genetic screening in general?
It was not until the 1990s when DNA sequencing of HCM pedigrees led to the discovery of variants in genes coding for sarcomere proteins were co-inherited in patients with LVH. Thus, HCM since has been regarded as a monogenic cardiac disease.The two most common genes with damaging variants are beta myosin heavy chain (MYH7) and myosin-binding protein C3 (MYBPC3).70% of variant-positive patients have gene variants in these genes; however, it is important to recognize that many patients with HCM are currently without any identifiable pathogenic genetic etiology to their disease (40 to 60% of patients depending on the study).Thus, genetic testing is crucial to the diagnosis and management of HCM, especially to inform cascade testing in family member and preconception and prenatal genetic counseling. As has been discussed previously on the CardioNerds podcast, appropriate pre- and post-test genetic counseling is necessary to ensure patients and their families understand the medical, social, psychological, ethical and professional implications of having a genetic disease, underscoring the value of multidisciplinary HCM centers.
How do we apply the guidelines regarding genetic screening to our patients?
As was done in this case, a detailed family history of at least three generations regarding HCM and SCD events should be taken. Typically, genetic testing for HCM is first done in the family member with clear phenotypic evidence of HCM – the index case. The 2020 ACC/AHA HCM guidelines nicely outline subsequent testing based on whether a variant is pathologic (Figure 1) Please remember to review the Guidelines yourself as it is a comprehensive text that provides key details not covered here!However, the index case could not afford genetic testing and the pathology available to us was not definitive for HCM. Postmortem testing for HCM-associated variants using blood or tissue samples collected at autopsy is possible, but access to a molecular autopsy and insurance coverage can vary significantly based on jurisdiction.Our patients (the brothers in their 20s) were arriving without genetics to inform their screening. In this circumstance we utilize Figure 2 (below) from the guidelines and would consider the index patient (the mother) phenotype negative. And since no variant was identified in the index patient, we would likely offer screening ECG/Echo (or cardiac MRI) to the brothers and follow up with clinical surveillance with imaging/ECG every 3-5 years.
How do we decide if a variant is pathogenic?
The pathogenicity of variants is based on American College of Medical Genetics and Genomics criteria and can actually change over time. As Dr. Kittleson noted, there are fewer quality genetic data in non-white HCM populations.The five highest frequency variants for HCM in the Human Gene Mutation Database of the NHLBI Exome sequencing Project were more frequent in Black Americans vs. White Americans which could lead to false positive diagnoses of HCM in Blacks. Furthermore, a lack of diverse racial/ethnic control populations could lead to a misclassification of benign variantsAs Dr. Kittleson noted on #CardsRounds, this again highlights the importance of multidisciplinary HCM clinics that have the expertise to periodically re-evaluate the pathogenicity of variants. If they a particular variant has been reclassified (either upgraded or downgraded), it would affect cascade testing and clinical surveillance in families.
Case #2 Synopsis: