William M. DeCampli and Kamal K. Pourmoghadam The Heart Center at Arnold Palmer Hospital for Children, Orlando, FL, USA Hypertrophic cardiomyopathy (HCM) may be defined as left ventricular (LV) hypertrophy in the absence of a hemodynamic cause such as excessive LV afterload. In this setting, the definition of hypertrophy is commonly taken to be echocardiographic or magnetic resonance imaging of a maximal diastolic septal or LV wall thickness >15 mm in adults and a z‐score ≥ adjusted for height and weight in infants and children. The hypertrophy can be progressive, with or without LV outflow tract obstruction (LVOTO), leading to myocardial ischemia, arrhythmias, and heart failure, together with their symptoms of angina, syncope, dyspnea, and sudden cardiac death. In children, HCM is really a heterogeneous group of disorders. Lipshultz and colleagues have suggested the following functional phenotypes of HCM: isolated HCM, mixed hypertrophic and dilated cardiomyopathy, and mixed hypertrophic and restrictive cardiomyopathy [1]. A small number of children, especially infants, may present with biventricular obstruction. Isolated HCM is further subgrouped as idiopathic HCM, HCM with malformation syndromes, HCM with inborn errors of metabolism, HCM with neuromuscular disease, and familial HCM. The nonidiopathic forms include the syndromes associated with mutations in genes that code for proteins of the Ras/mitogen activated protein kinase (MAPK) pathway, such as Noonan and Costello syndromes, glycogen storage diseases such as Pompe and Danon (LAMP2) diseases, PRKAG2 mutations, Fabry disease, Leopard and Kabuki syndromes, and rare mitochondrial myopathies [2, 3]. The majority of cases of HCM, however, are isolated and either idiopathic or familial. Idiopathic/familial HCM is commonly associated with mutations in genes encoding the thick and thin contractile myofilament protein components of the sarcomere or Z discs. In one study of 474 patients with idiopathic or familial HCM, 187 had a positive family history, and 72 were genotyped to sarcomere protein mutations [4]. The most common genes affected are those encoding synthesis of the myosin‐binding protein C and the beta‐myosin heavy chain [3]. The mutation is inherited in an autosomal dominant pattern with variable penetrance. A number of studies have examined the natural history and outcomes of children diagnosed with isolated HCM [1, 2, 5]. Historically, the risk of death has been significantly greater than that of adults with HCM. In a study of 958 pediatric patients (<18 years old) from the Pediatric Cardiomyopathy Registry Study Group, Lipshultz and colleagues determined risk factors at the time of diagnosis for subsequent death or transplantation [1]. Poorest outcomes at 1 year follow‐up were seen in children with inborn errors of metabolism (event rate 48% [95% confidence interval (CI) 36–60%]), in those with mixed hypertrophic/dilated phenotype (event rate 43% (95% CI 31–55%]) and mixed hypertrophic/restrictive phenotype (event rate 30% [95% CI 18–42%]). On the other hand, excellent outcomes were seen in 407 patients with idiopathic HCM diagnosed at >1 year old (event rate 1% [95% CI 0–2%]). In patients <1 year old at diagnosis with idiopathic HCM, the multivariable regression showed that lower weight, younger age, presence of congestive signs, and greater end‐diastolic wall thickness were risk factors for an event. Patients with two or more of these risks had an event rate of 38% at 2 years. HCM is the most common cause of sudden cardiac death in the young (including competitive athletes). Risk factors for sudden cardiac death in HCM have been developed for teenagers and adults, but not definitively for younger children [5]. In teenagers, these risk factors include prior cardiac arrest, nonsustained ventricular tachycardia, massive LV hypertrophy (wall thickness >30 mm), syncope, blunted systolic blood pressure response to exercise, and first‐degree family history of sudden cardiac death. More recently, criteria based on electrocardiogram (ECG) morphology, including exercise‐induced quantitative microvolt T‐wave alternans, have been considered for use in the pediatric population [6–8]. The risk of sudden cardiac death in infants and toddlers is low, but rises and peaks in the 8–16‐year age group. The risk is greater with intense exercise, leading to the recommendation that HCM patients with certain risk factors should not participate in competitive sports [9]. The treatment for HCM in children almost always begins with pharmacologic management, most commonly beta blockers or calcium antagonists. These agents, by reducing heart rate and contractility, improve coronary flow/demand ratio, decrease LVOTO gradient, improve diastolic filling, and reduce symptoms. Less frequently, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, or disopyramide may be used. Dual‐chamber pacing has been used with mixed success and currently is indicated only in specific subsets of adult patients [10, 11]. Exercise restriction and implantable cardioverter‐defibrillator (ICD) therapy are used when risk factors for sudden cardiac death are present (see above). Septal myectomy (or sometimes alcohol septal ablation in adults) is reserved for symptoms refractory to pharmacologic therapy in the presence of significant LVOTO. This may be accompanied by repair of the mitral valve or, rarely, mitral valve replacement (see below). Heart transplantation is considered when HCM progresses to end‐stage heart failure. In 2016 Maron and colleagues published a study of 474 pediatric and young adult patients (age 7–29 years) with idiopathic/familial HCM presenting at two referral institutions [4]. Interventions and outcomes were followed (median 6.0 years, interquartile range 3–10 years). Only 10 patients were less than 10 years old at initial presentation. Essentially all patients were on drug therapy, 231 had received ICDs, 54 had undergone myectomy or alcohol septal ablation, and 18 underwent heart transplantation. Overall Kaplan–Meier survival at 10 years was 94% (95% CI 90%–97%). The clinical outcomes are shown in Figure 31.1, and the Kaplan–Meier curves for freedom from mortality or from aborted life‐threatening events are shown in Figure 31.2. The authors demonstrated that the event rate (0.54%/year) in this population was similar to that of large adult studies, and ascribed this to the effective use of the above treatment modalities. HCM is frequently associated with a gradient across the LVOT. In HCM, LVOTO is currently defined as a peak instantaneous continuous wave Doppler gradient or peak‐to‐peak catheter gradient >30 mmHg either at rest (basal) or with physiologic provocation. The threshold for considering intervention on LVOTO is currently defined as a gradient >50 mmHg [10, 11]. The prevalence of LVOTO is significant. Among 320 patients (ages 13–86 years) seen prospectively over an 18‐month period, 119 (37%) had a resting gradient >50 mmHg [12]. Hickey and associates showed that of 120 pediatric patients (age <22 years) with HCM, the prevalence of LVOTO was 50% [13]. Additionally, Maron and colleagues found that among patients with a resting gradient <50 mmHg, 38% of these patients developed a gradient >50 mmHg with exercise [12]. Numerous studies have examined the nature of this obstruction [14, 15]. The principal sources of the gradient are systolic anterior motion (SAM) of the anterior (and occasionally posterior) mitral leaflet (AML), midcavity septal‐to‐free wall contact during part of systole, obstructive anomalous papillary muscles or mitral chords attached into the LVOT, and rarely apical obstruction. The anatomic substrate is illustrated in Figure 31.3. Mitral regurgitation (MR) is associated with LVOTO and SAM. Hickey and colleagues found SAM in 55% of pediatric patients with LVOTO (>30 mmHg at rest), and moderate or severe MR in about 10% of obstructed patients [13]. Mitral valve abnormalities causing SAM and MR include (i) anterior and basilar displacement of base of the anterolateral papillary muscle (ALPM) in the LVOT, often with fusion of some length of the ALPM to the LVOT free or septal wall and direct insertion of its head onto the middle of the AML; (ii) accessory papillary muscle with origin on the septal wall of the LVOT with direct insertion onto the middle of the AML; (iii) abnormal muscular connections between the head of the ALPM and the anterolateral wall, inserting into or near the A1 scallop; (iv) AML elongation; (v) fibrotic retracted secondary chordae; and, rarely, (vi) isolated elongation of the posterior mitral leaflet [15]. Figure 31.1 Diagram summarizing clinical outcome in 474 children, adolescents, and young adult hypertrophic cardiomyopathy (HCM) patients 7–29 years of age at study entry. *16 events occurred before the first evaluation by 1.3 (0.6, 4.7) years; range 3 days–11.4 years, including 13 resuscitated out‐of‐hospital cardiac arrests and 3 appropriate implantable cardioverter‐defibrillator (ICD) interventions. **Includes out‐of‐hospital resuscitated cardiac arrest (RCA; n=9); RCA followed by appropriate secondary prevention ICD interventions (n=9); RCA with subsequent appropriate secondary preventions and followed by transplant (n=2). †Died 0.9, 1.1, and 1.5 years after transplant. ‡Includes 1 patient with heart transplant, 4 months after ICD intervention. Rhabdomyolysis and liver failure secondary to statin therapy, died awaiting transplant (n=1); automobile accident (n=1). Source: [4] / with permission of Wolters Kluwer Health. The significance of LVOTO in HCM is that in adults, it is an independent predictor of adverse clinical consequences, including progressive heart failure and death [16, 17]. The evidence for this relationship is weaker in the pediatric population, but is generally accepted to hold. Ommen and associates showed that surgical myectomy in adults was associated with long‐term survival equivalent to the general population and better than a matched cohort with HCM and LVOTO managed without operation [18]. This finding has been corroborated in other studies [19]. In adults and in older children, relief of LVOTO significantly improves HCM‐related symptoms [18, 20, 21]. For example, Orme and colleagues showed that in patients with HCM, LVOTO, and syncope, myectomy reduced the incidence of recurrent syncope and improved survival compared to a control group [21]. Consequently, the guidelines for surgical myectomy are currently similar to those in adults, namely, (i) resting or provoked gradient >50 mmHg with symptoms despite optimal pharmacologic therapy, or (ii) gradient >85 mmHg with demonstrated reduced functional aerobic capacity even if asymptomatic. In infants and toddlers the evidence base for formal recommendations for myectomy is not as solid, as published studies focused on this age group are still lacking. Alcohol septal ablation is controversial and has not been widely used in the pediatric population, owing to technical challenges and absence of knowledge of long‐term complications of the procedure [11]. Figure 31.2 Kaplan–Meier survival curves in 474 children, adolescent, and young adult hypertrophic cardiomyopathy (HCM) patients, with relevant comparisons between subgroups and to expected all‐cause mortality in the US general population matched for age and sex. (A) HCM‐related mortality in 474 HCM patients vs. all‐cause mortality in the general population; dotted lines denote 95% confidence interval. (B) HCM‐related mortality combined with life‐threatening HCM events aborted by major treatment interventions vs. HCM mortality. The survival difference between the two curves describes the effect of treatment interventions. The 16 patients with cardiac arrest or appropriate implantable cardioverter‐defibrillator (ICD) interventions before the first visit are excluded from this analysis. CI, confidence interval; SMR, standardized mortality ratio. Source: [4] / with permission of Wolters Kluwer Health. Figure 31.3 Hypertrophic cardiomyopathy with left ventricular outflow tract (LVOT) obstruction. Obstruction occurs as a result of (i) ventricular hypertrophy, particularly the septum, and (ii) displacement of the mitral apparatus into the LVOT. In early systole, these factors deviate the flow so as to lift the mitral anterior leaflet into the LVOT (systolic anterior motion). Source: Reproduced with permission from Messmer BJ. Oper Tech Thorac Cardiovasc Surg. 2004;9:268–277. Cleland first reported the management of HCM by myectomy in 1963, and Morrow and colleagues published the first series reporting encouraging outcomes [22, 23]. Myectomy was reported in infants in the early 1970s and anecdotal reports of survival appeared by the 1980s [24–26]. In 2005, the Mayo Clinic group published results of 56 pediatric patients undergoing myectomy, with actuarial 10‐year survival of 93% [27]. This group (Danielson, Dearani, Schaff, and others) has accumulated one of the world’s largest experiences with HCM in all age groups. The goals of surgery for HCM are to relieve LVOTO by resecting obstructive tissue and by eliminating SAM, and to render the mitral valve competent. In the operating room, postrepair echocardiography should show a residual gradient (as defined above) <10 mmHg, absence of SAM, and at most mild MR. In most cases, if one enlarges the LVOTO by resection, then SAM will be eliminated. Furthermore, if SAM is eliminated then the degree of MR will be significantly reduced or eliminated [19]. The appropriate approach to each patient is to thoroughly assess all significant abnormalities of the LVOT and mitral valve preoperatively, then address each at the time of operation. Consequently, the generic operation has evolved from the simple Morrow myectomy to a more complex and patient‐specific procedure, frequently called extended myectomy, for which there are several variants [28]. Herein is described the technique used at our institution, which integrates several of these variants. An echocardiogram should be obtained and views and measurements made in accordance with the most current guidelines of the American Heart Association Foundation/American College of Cardiology or of the European Society of Cardiology [10, 11]. The surgeon should make note of the recommended measurements listed in Table 31.1. Table 31.1 Echocardiographic measurements used for assessment of hypertrophic cardiomyopathy.
CHAPTER 31
Hypertrophic Cardiomyopathy
Definition, Classification, Etiology, and Diagnosis
Natural History
Treatment
Outcome
Hypertrophic Cardiomyopathy with Left Ventricular Outflow Tract Obstruction
Operative Management of Hypertrophic Cardiomyopathy with Left Ventricular Outflow Tract Obstruction
Preoperative Echocardiography
Normal (z=0) septal and free wall thicknesses for age and height
Peak instantaneous gradient at rest and with provocation
Location of gradients (subvalvar, midcavity, apical)
Aortic annulus diameter
Aortic valve morphology
Distance from the annulus to the “friction lesion” (point of contact between the septum and anterior mitral leaflet [AML] in systole)
Distance from the annulus to the apical extent of the septal bulge
Maximal basal, mid, and apical septal thicknesses in systole and diastole
Free wall thickness in systole and diastole
Mitral annulus diameter and z‐score
Mitral morphology, including length (with z‐score) of the AML 
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