Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

Figures & data

Figure 1 Phenotypic subtypes of hypertrophic cardiomyopathy, differentiated by region of hypertrophy. (A) Representation of a normal human heart. (B) Type A/type I hypertrophy results in a sigmoid septum with discrete hypertrophy of the basilar septum with less severe hypertrophy of the basolateral wall. (C) Type B/Type II hypertrophy involves the majority of the basilar septum and in three dimensions spirals anteriorly as it tracts down to the apex. (D) Type C hypertrophy (a subclass of Type III hypertrophy) denotes primarily uniform hypertrophy of both the septum and the posterior wall. (E) Type D (a subclass of Type IV hypertrophy) primarily involves the apex with minimal hypertrophy in the septum or posterior wall. (F) Type E (a subclass of Type III hypertrophy) involves both the septum and the posterior wall with minimal apical involvement and can lead to mid-cavitary gradients.

Table 1 Genes Responsible for the Development of Hypertrophic Cardiomyopathy

Gene	MOI	Protein	Function	Percent of Cases
MYBPC3^+	AD	Myosin-binding protein C	Cardiac contraction	50–60
MYH7^+	AD	β-Myosin heavy chain	Sarcomere force generation	20–30
TNNI3^+	AD	Cardiac troponin I	Inhibitor of actomyosin interaction	3–5
TNNT2^+	AD	Cardiac troponin T	Regulator of actomyosin interaction	2–3
TPM1^+	AD	α-Tropomyosin	Places troponin complex on cardiac actin	<5
MYL2^+	AD	Myosin light chain-2	Role in cross-bridge cycling kinetics	2–5
MYL3^+	AD AR	Myosin light chain-3	Regulatory light chain of myosin	<1
ACTC1^+	AD	Cardiac α-actin	Actomyosin interaction	<1
PLN^+	AD	Phospholamban	Regulates calcium pump in cardiac myocytes	<3
TPM1^+	AD	α-Tropomyosin	Places the troponin complex on cardiac actin	<3
CSRP3*	AD	Cysteine and glycine-rich protein 3	Muscle LIM protein, a Z disk protein	<1
ACTN2*	AD	Actinin, alpha 2	Z-disk protein	<1
TNNC1*	AD	Cardiac troponin C	Calcium-sensitive regulator of myofilament function	<1
TRIM63^#	AD	Muscle ring finger protein 1	E3 ligase of proteasome ubiquitin system	Rare
MYOZ2^#	AD	Myozenin 2 (calsarcin 1)	Z-disk protein	<1
MYH6^#	AD	(α)-Myosin heavy chain	Cardiac contraction	Rare
TTN^#	AD	Titin	Sarcomere function	Rare
ACTN1^#	AD	Actinin, alpha 1	Z-disk protein	Rare
MYH6^#	AD	α-Myosin heavy chain	Sarcomere force generation	Rare
TCAP^#	AD	Telethonin	Z-disk protein	Rare
VCL^#	AD	Vinculin/metavinculin	Intercalated disk protein	Rare
RYR2^#	AD	Ryanodine receptor 2	Calcium-induced calcium release	Rare
JPH2^#	AD	Junctophilin 2	Sarcoplasmic reticulum-surface membrane binding protein	Rare

Notes: +Denotes gene mutations that have definitive evidence of HCM causation; *Denotes genes with moderate evidence of HCM causation; #Denotes genes with limited evidence of HCM causation.

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MOI, mode of inheritance.

Figure 2 Left ventricle to aortic root angulation and its impact on left ventricular outflow tract gradient. (A) In structurally normal hearts, the left ventricular to aortic root angle (LVARA) is greater than 140°. (B) With septal hypertrophy, the LVARA decreases, and more blood is directed toward the anterior leaflet of the mitral valve. This is thought to promote a Venturi effect and drag forces that increase the left ventricular outflow tract gradient and promote systolic anterior motion of the mitral valve.