B P6 C54 Hypertrophic Cardiomopathy Flashcards
Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium.
It is defined by the presence of _____.
- Unexplained left ventricular hypertrophy (LVH) * Absence of identifiable factors that may account for increased left ventricular wall thickness, including pressure overload and infiltrative or storage disorders
Classically, _____ are present histologically
- Myocyte hypertrophy
- Disarray
- Myocardial fibrosis
Familial disease is well characterized, and pathogenic variants in the genes encoding the cardiac _____ are the most common etiology of HCM
Sarcomere
A maximum left ventricular wall thickness of ≥15 mm has been the standard threshold to diagnose disease in adults, although a threshold of≥13 mm is recommended if there is a family history of HCM or if the individual in question carries a disease-causing (pathogenic) sarcomeric gene variant.
MAXIMUM LV WALL THICKNESS
Standard: ≥ 15 mm
Family hx of HCM: ≥ 13 mm
At the histopathologic level, HCM is characterized by myocyte hypetrophy, disarray, and fibrosis. These intrinsic tissue abnormalities, particularly _____, likely contribute to clinical manifestations of heart failure (systolic and diastolic) and to the genesis of arrhythmias (ventricular and atrial)
Myocyte hypertrophy
Myocardial fibrosis
The location and degree of hypertrophy are variable, and ventricular volumes are typically small. Although _____ is the classic and most common morphologic subtype of HCM, hypertrophy can involve any left ventricular (LV) segment and may be focal or concentric
Asymmetric septal hypertrophy resulting in reversed septal curvature
Apical HCM is a well-described morphologic variant in which hypertrophy involves the _____.
Distal LV, below the level of the papillary muscles
As such, apical HCM is NOT associated with left ventricular outflow tract obstruction (LVOTO).
Apical HCM was first reported in Japan and is more prevalent in individuals of Japanese versus European descent (13% to 25% vs. 1% to 2%). Although early studies suggested a more benign prognosis for apical HCM, a broad spectrum of clinical outcomes has been described.
Patients with classic reversed septal curvature are most likely to have _____ whereas patients with a sigmoidal septum (discrete upper septal thickening) or apical hypertrophy are least likely to have sarcomeric disease. This latter pattern of hypertrophic remodeling is relatively common in older adults with hypertension and thus nonspecific.
Pathogenic sarcomeric gene variants
The differential diagnosis for HCM includes other conditions that may also result in increased left ventricular wall thickness, including _____.
- Syndromic, metabolic, storage, or infiltrative disorders (e.g., Noonan syndrome/RASopathies, Fabry disease, Pompe disease, cardiac amyloidosis, mitochondrial disease)
- Compensatory or secondary hypertrophic heart disease attributed to pressure overload (hypertension) or intense athletic training
Seminal genetic studies performed on families with HCM in the 1980s to 1990s established that HCM is a disease of the sarcomere—most frequently caused by pathogenic variation in genes encoding cardiac-specific sarcomeric proteins, particularly _____.
Myosin binding protein C (MYBPC3) - 55%
Myosin heavy chain (MYH7) - 32%
Troponin T (TNNT2)
Troponin I (TNNI3)
Myosin light chains (MYL2 and MYL3)
Alpha-tropomyosin (TPM1)
Actin (ACTC)
Variants in _____ are most common; collectively responsible for over 80% of sarcomeric HCM (caused by pathogenic sarcomeric variants identified by genetic testing)
MYBPC3 (55%) and MYH7 (32%)
The population prevalence of ___ is approximately 1:500, making it the most common monogenic heart disease
HCM
At the cellular level, abnormal calcium handling and altered interaction between actin-myosin has been identified, leading to abnormal _____.
Contraction and relaxation
Coupled with the inherent stiffness of the hypertrophied left ventricle, some degree of _____ dysfunction is present in nearly all patients with HCM
Diastolic dysfunction
Early diastolic tissue Doppler velocities are _____ in most patients with HCM, and abnormalities can be identified before the development of overt LVH in individuals who carry pathogenic sarcomeric variants
Reduced
Because the capillary network is less dense in HCM, _____ ischemia is readily manifest and can further worsen diastolic function.
Subendocardial ischemia
Moreover, calculated LVEF may not be a reliable measure of overall systolic function in HCM as the small LV cavity size associated with HCM is in the denominator of the formula and may artificially elevate ejection fraction. Accordingly, patients with HCM are considered to have significantly impaired systolic function if the ejection fraction less than _____%.
< 50%
The most clinically apparent, and treatable, pathophysiologic mechanism in HCM is that of _____.
LVOTO
Obstruction is present at rest or with physiologic provocation in up to two-thirds of patients with HCM and occurs as the hypertrophied septum redirects flow across, rather than along the mitral valve, which causes _____, further narrowing the outflow tract.
The mitral valve itself is often elongated and positioned more _____, which amplifies this effect
Systolic anterior motion (SAM)
Anteriorly
The anterior mitral leaflet, rather than closing normally, is pushed further into the outflow tract, narrowing the latter and interfering with coaptation.
Together, this results in increased ____ and _____, particularly in late systole, increased _____, and _____ directed mitral regurgitation
Increase:
LV systolic pressure
Obstruction to flow (Late systole)
Increased myocardial O2 demand
Posteriorly directed MR
Patients are considered to have obstructive physiology if they have maximum instantaneous gradients across the outflow tract of at least _____ mm Hg.
Resting or provoked gradients exceeding ____ mm Hg are considered capable of causing limiting symptoms.
Patients with effort-related symptoms and resting LVOT gradients less than ___ mm Hg should have provocative maneuvers included with noninvasive evaluation
MIG:
30 mm Hg
Resting or provoked gradients > 40-50 mm Hg (limiting symptoms)
Symptoms + Resting LVOT gradient < 40 mm Hg
-> Provocative maneuvers
Bedside maneuvers such as _____ can be helpful in identifying latent outflow obstruction.
Provocation with exercise (e.g.,exercise echocardiography) is a highly relevant and physiologic method to assess effort intolerance and should be considered in patients with symptoms whose resting gradients are not sufficiently high to account for their symptoms
Valsalva or squat-to-stand
Aggressive ____ or restoration of _____, both in combination with oral anticoagulation are felt to be important for patients with HCM
Rate control
Sinus rhythm
Overall morbidity in HCM is dominated by heart failure and atrial fibrillation. Similarly, mortality is driven by complications of _____, both of which are more common than lethal arrhythmias
Heart failure and noncardiac death
Sex also impacts the clinical course in HCM. _____ are typically diagnosed at an older age and typically have more symptomatic heart failure and higher mortality.
Females
The majority of these HCM-related complications occur later in life, becoming most prevalent by _____ adulthood, even in patients diagnosed before age 40 years
Middle to late adulthood
For adult and adolescent first-degree relatives of patients with HCM, screening is recommended to commence at the _____.
- Time of diagnosis in the proband
- Repeated at regular intervals
Late childhood - adolescence: every 1 to 2 years
Adulthood: every 5 years
Persistent symptoms beyond this prompts consideration of advanced options including _____.
Disopyramide (added to one of the other agents)
Class IIa indication of ICD implantation in patients with HCM
NO Prior event of SCD, VF or sustained VT
With at least 1 of the following:
* FH SCD
* Massive LVH
* Unexplained syncope
* Apical aneurysm
* EF less than or equal to 50%
* Nonsustained VT in children
