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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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.

1. 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.
   
2. 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.
   
3. 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?

1. 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.
   
2. 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).
   
3. 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!
   
4. 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?

1. 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.
   
2. 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).
   
3. 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?

1. 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.
   
2. 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 variants
   
3. As 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:

In this second case on HCM #CardsRounds, we saw a young woman in her 20s who was seeking a 2^nd opinion regarding primary prevention ICD. She was diagnosed with HCM three years ago after a murmur was discovered on exam. Her echo demonstrated a septal wall thickness of 1.9 cm, LVOT gradient at 23 mmHg at baseline and 126 mmHg with treadmill stress. She was eventually referred for myectomy where 11 grams of myocardium was resected and her gradients improved significantly. She did well for two years and then had multiple syncopal episodes in the setting of a GI illness. Her repeat echo showed a maximal wall thickness of 2.6 cm, no LVOT obstruction at rest or provocation. She was referred for an ICD but wanted a 2^nd opinion. You discover she does have a likely pathologic variant in the MYH7 gene, and both her mother and son have the variant. Her mother had NSVT and so will be receiving an ICD. She had a maternal half-brother who passed away from possible overdose but autopsy was suggestive of HCM (with genetic testing still in the works). She underwent a 7-day Holter with no NSVT. Just before this visit she had an MRI which suggested 8-12% late gadolinium enhancement, a hypertrophied septum and LV apical wall thinning (likely not a true aneurysm).

Case #2 Quotes:

“Let’s talk about Sudden Death risk stratification in HCM, or basically, how do you predict the future?”

• Dr. Kittleson reviewing the 2020 guidelines
  

 “If something doesn’t make sense. You go to the source! Speak to your whole team. Help me, help you, help the patient!”

• Dr. Kittleson On utilizing multidisciplinary HCM team to inform patient care
  

 “One fantastic component of the 2020 HCM guidelines is the explicit recommendation for shared decision-making with a full disclosure of risks, benefits, anticipated outcomes and the patient expresses their goals and concerns. But let us not forget, that shared decision-making is not an excuse to abdicate medical decision making. It is still your responsibility to provide a medical recommendation … and then work with the patient to see how that medical opinion fits in with the patient’s values and goals.”

• Dr. Kittleson on shared decision-making on ICD placement
  

 Takeaways Case #2

How do we make a decision for ICD in HCM patients? How do the new guidelines differ?

1. HCM is considered the most common cause of SCD in young people in North America, and thus much research has gone into defining the clinical features that would justify a primary prevention ICD in HCM patients.
   
2. There are important differences between the 2011 and 2020 guidelines in regards to clinical factors to consider, as outlined below.
   
3. Similar in Both Guidelines (Typically applying to Adults <60 years old*)
   
   1. A history of sudden cardiac death, ventricular fibrillation or sustained VT is a Class I indication for secondary prevention ICD in patients with HCM in both guidelines.
      
   1. Family history of SCD from HCM (Class IIa in 20211 and 2020) is defined as sudden death attributable (or likely attributable) to HCM in ≥ 1 first-degree or close relatives who are ≤ 50 years of age. Close relatives are generally considered to be second-degree relatives.
      
   1. Massive LVH (Class IIa in 2011 and 2020), in adults patients is defined as wall thickness ≥ 30 mm in any segment by echo or cardiac MRI
      
   1. Unexplained Syncope (Class IIa in 2011 and 2020) is defined as ≥ 1 unexplained episodes of syncope, unlikely to be of neurocardiogenic etiology or attributable to LVOTO
      
   1. Apical Aneurysm (Class IIa in 2011 and 2020) is defined as a discrete thin-walled dyskinetic or akinetic segment of the most distal portion of the LV
      
   
   
4. Differences in the Guidelines (Typically applying to Adults <60 years old*)
   
   1. Previously in the 2011 guidelines, the presence of abnormal BP response to exercise + either (1) genetic mutations and/or (2) LVOTO > 30 mmHg was considered a Class IIa indication for an ICD. These criteria have been removed from the 2020 guidelines.
      
   1. In the 2020 guidelines, there is a new emphasis on systolic dysfunction with EF < 50% by echo or cardiac MRI, and it is given a Class IIa indication for an ICD.
      
   1. NSVT – defined as frequent (≥3), longer (≥10 beats), and fast (≥200 bpm) occurring usually over 24 to 48 hours – was a Class IIa indication for an ICD in the 2011 guidelines and has been de-emphasized in the 2020 as a Class IIb.
      
   1. Extensive late gadolinium enhancement (LGE) on CMR is defined as diffuse and extensive LGE quantified or estimated as compromising ≥ 15% of the LV mass
      
   
   

 How often should we screen for clinical factors that would increase risk for SCD? What are some nuances we should be aware of?

1. As with most decisions in medicine, the patient should be at the center of the decision-making process regarding ICD. For some patients, they may want a quantifiable estimate of their SCD risk, which can be estimated with a 5-year SCD Risk Calculator. Of note, certain contemporary SCD risk markers are not included in these calculators, including systolic dysfunction, LGE on MRI, or LV apical aneurysm.
   
2. SCD risk assessment should occur at the initial visit and then be repeated every 1 to 2 years as part of the ongoing clinical surveillance of HCM. Of note, the data suggests a lower SCD event rate in older patients with HCM (>60 years of age), and thus the decision regarding continuing risk assessment in this population is individualized.
   
3. As noted above, several criteria are dependent on imaging – including LV wall thickness. This may be underestimated on echocardiography compared to cardiac MRI and MRI adds the additional component of assessing LGE
   

 Based on the above criteria, how would you advise our patient?

1. She does not meet a Class I indication for ICD.
   
2. In regards to Class IIa recommendations, she does not have massive LVH, unexplained syncope, likely does not have an apical aneurysm, and has a normal LVEF.
   
3. The family history is questionable given her half-brother’s death under unclear circumstances with morphologic evidence of HCM on autopsy. Given the concerning family history, she may have a Class IIa reason to pursue an ICD.
   
4. However, she also does not have NSVT and does not have extensive LGE – though this is in the setting of being post-surgical myectomy.
   
5. After shared-decision making, given the constellation of findings it would be reasonable to offer her an ICD.
   

Case #3 Synopsis:

A woman in her early 30s comes to an HCM Center of Excellence to establish care. She was diagnosed with HCM without obstruction one year prior. She initially presented with exertional dyspnea, and eventually MRI revealed HCM without obstruction, maximal wall thickness with 2.5 cm and no LGE. Her father passed away at age 50 from an “MI.” Her genotyping was negative. Soon after she was having recurrent episodes of syncope and a loop recorder was placed. She came for follow was now 4 months pregnant. Just before the visit she felt pre-syncopal and Loop revealed SVT at rates of 150s. Then at 6 months pregnant, patient had one 10-beat run of NSVT at rate of 180 bpm. How would you advise this patient?

 Case #3 Quotes:

“One of my most important ways of preventing burnout in medicine – is to phone a friend, to ask for help, to talk about cases with trusted colleagues.”

• Dr. Kittleson on how to approach complex cases
  

Case #3 Takeaways:

 How does HCM care differ in pregnant patients per the guidelines?

1. In most pregnant women with HCM, selected beta-blockers should be given for symptoms related to LVOTO or arrhythmias with monitoring of fetal growth (Class I). Note atenolol has some evidence of potential fetal risk.
   
2. In terms of delivery, Valsalva during labor has generally been shown to be well tolerated. Cesarean section should typically only be done for obstetric reasons or for emergency cardiac/maternal reasons. As discussed in our Cardio-Ob series, a delivery plan should be developed by a multi-disciplinary team by the end of the second trimester
   
3. Most antiarrhythmic medications are contraindicated during pregnancy because of the potential teratogenic effects, and typically many are not recommended for patients with HCM. Cardioversion can typically be performed safely in pregnancy with minimal risk to the fetus and thus may be preferred for restoring sinus rhythm in symptomatic pregnant women with HCM.
   

How would you advise this patient regarding ICD?

1. It appears she may have a Class IIa recommendation for ICD if you believe the family history is actually positive for sudden cardiac death, otherwise she likely does not have an indication for ICD. The NSVT was present but it was one episode, not at a fast rate (<200 bpm) and thus likely does not reach to the level of recommending an ICD. Furthermore, the syncope appears attributable to SVT rather than ventricular arrhythmia.
   
2. Implantation ICD for primary prevention can typically wait until after pregnancy
   

Figure 1:

Figure 2

1. Ommen SR, Mital S, Burke MA et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e558-e631. doi: 10.1161/CIR.0000000000000937. Epub 2020 Nov 20. Erratum in: Circulation. 2020 Dec 22;142(25):e633. PMID: 33215931.
   
2. Maron BJ. Clinical Course and Management of Hypertrophic Cardiomyopathy. N Engl J Med. 2018 Aug 16;379(7):655-668. doi: 10.1056/NEJMra1710575. PMID: 30110588.
   
3. Manrai AK, Funke BH, Rehm HL et al. Genetic Misdiagnoses and the Potential for Health Disparities. N Engl J Med. 2016 Aug 18;375(7):655-65. doi: 10.1056/NEJMsa1507092. PMID: 27532831; PMCID: PMC5292722.
   
4. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011 Dec 13;58(25):e212-60. doi: 10.1016/j.jacc.2011.06.011. Epub 2011 Nov 8. PMID: 22075469.
   
5. Maron BJ, Casey SA, Olivotto I et al. Clinical Course and Quality of Life in High-Risk Patients With Hypertrophic Cardiomyopathy and Implantable Cardioverter-Defibrillators. Circ Arrhythm Electrophysiol. 2018 Apr;11(4):e005820. doi: 10.1161/CIRCEP.117.005820. PMID: 29625970.
   

• 
  Karan Desai, MD
  
  
• 
  Natalie Stokes, MD
  
  
• 
  Amit Goyal, MD
  
  
• 
  Daniel Ambinder, MD