Hypertrophic cardiomyopathy (HCM) is characterized by LV hypertrophy ≥ 15 mm without an identifiable cause (no valvular disease, no hypertension, or the degree of hypertrophy is disproportionate to the severity of hypertension). The prevalence in the general population is 1 in 500. HCM is genetic. It is familial, autosomal dominant, in 50% of the cases, with high penetrance; the remaining 50% are due to new mutations. The septal thickness is usually greater than 15 mm (13–14 mm is diagnostic if family history of HCM or positive genetic test). The hypertrophy is usually asymmetric and involves the septum and the anterolateral wall with a septal-to-posterior wall thickness ratio of >1.3:1, and more specifically >1.5:1, but it may be symmetric and diffuse, involving the posterior wall in 10–20% of the cases (= concentric hypertrophy).1–3 One report suggests that the posterior wall is involved in cases of diffuse hypertrophy,3 while another report suggests that posterobasal wall involvement is very unusual even when hypertrophy is diffuse.4 Either way, the posterior wall is the site least frequently thickened in HCM. Hypertrophy most often involves two or more myocardial segments in an asymmetric and sometimes “bumpy” fashion, but may involve only one segment. Severe LVOT obstruction leads to severe afterload elevation that may result in a global LV hypertrophy with time; hence, septal reduction not only reduces septal thickness but also the LV thickness at distant segments. When obstructive, HCM is called hypertrophic obstructive cardiomyopathy (HOCM) and is usually characterized by septal hypertrophy that narrows the left ventricular outflow tract (LVOT). The increased velocity across the LVOT draws the anterior mitral leaflet and its chordae during systole, which further narrows the LVOT and creates LVOT obstruction. This process is called systolic anterior motion (SAM) of the anterior leaflet (both the leaflet edge and chordae). A significant obstruction is characterized by a resting gradient >30 mmHg or a gradient >50 mmHg with provocative maneuvers (peak instantaneous gradient).1,2 Only 30% of patients with hypertrophic cardiomyopathy have a resting gradient, while 45% have a gradient with provocative maneuvers; the remaining patients have non-obstructive hypertrophic cardiomyopathy. The gradient is within the LV, i.e., pressure is elevated throughout the LV body and a portion of the LVOT then drops at one point in the LVOT rather than across the aortic valve. On echo-Doppler, the velocity is increased across the point of LVOT obstruction and is decreased proximal to this point (LV inflow and mid-LV cavity) and distal to this point (aortic valve) (Figure 7.1). Mild or moderate MR is usually seen and is associated with SAM of the mitral valve. In up to 10% of HOCM cases, the hypertrophy and the obstruction may be mid-ventricular, as is the case with mid-ventricular HOCM, apical HOCM, or HOCM with anterolateral papillary muscle inserting directly onto the mitral leaflet. The marked septal hypertrophy may also contribute to RV outflow tract obstruction, particularly in children with HOCM. LVOT obstruction is associated with more symptoms and a higher HF-related mortality, but only a weak correlation with sudden death. MR is mainly related to SAM; it is directed posteriorly and peaks in mid and late systole (Figures 7.1–7.3).5–7 The severity of MR correlates with the severity of the LVOT gradient.5 MR may be severe (in ~10%) if the posterior leaflet is not elongated enough to meet with the “sucked” anterior leaflet. Severe MR with a relatively short posterior leaflet is expected to improve after myectomy, while severe MR despite an elongated posterior leaflet, or central or anteriorly directed MR, is concerning for a structural mitral abnormality.8 Figure 7.1 (a) Asymmetric septal hypertrophy with increased velocity across the LVOT (3 arrows). This increased systolic velocity drags the anterior mitral leaflet (SAM) and creates LVOT obstruction as well as a posteriorly directed MR (blue arrow). Note the anatomic contiguity of the mitral and aortic valves. Pulsed-wave Doppler should be used to sequentially interrogate the LV from apex up to the LVOT in order to confirm the anatomical level of obstruction. Note the normal velocity across the LV body, LVOT proximal to the obstruction and distal to it, and aorta (single arrows). (b) Pressure is increased throughout LV inflow, LV body, LVOT (+++), and drops beyond the LVOT obstruction (+). Even pressure at the mitral valve level (inflow tract pressure) is elevated. Figure 7.2 Parasternal long-axis view of a patient with HOCM, showing SAM of the anterior leaflet tip. Not just the leaflet gets drawn to the septum, but also the chordae (chordal SAM). Figure 7.3 M-mode of SAM. The star corresponds to the gap between the anterior and posterior leaflets in systole, leading to severe MR in this patient. (ii) and (iii) lead to tenting of the anterior leaflet anteriorly, into the LVOT stream. All these abnormalities facilitate SAM and LVOT obstruction, even in patients with milder degrees of septal hypertrophy ≤ 18 mm. Papillary muscle insertion directly on the anterior leaflet, without chordae, may cause LVOT obstruction (as it directly abuts the septum with each beat) and anterior tethering/MR. The HCM phenotype usually develops at the end of the second decade, and screening in adolescence may therefore miss it. Hypertrophy does not usually worsen in the adult. However, progressive global LV hypertrophy may develop as a result of the LVOT obstruction and increased LV workload, which leads to a vicious circle of more LVOT obstruction and LV hypertrophy. Approximately 5% of patients eventually succumb to this chronically elevated afterload and develop a late phase of LV cavity dilatation with reduced systolic function (burned-out phase of HCM). HCM onset may occur late, in the elderly. Moreover, it is not uncommon for an early HCM to present and be diagnosed late. In fact, in alcohol ablation studies, the median age was 64. In a cohort study, ~25% of HCM patients were elderly (≥75 years old).9 Elderly presentations are usually associated with milder LVH yet more obstruction. A population study has shown that the mortality of unselected HCM patients is ~1% per year, which is not different from the mortality of the general population.9 On the other hand, the annual mortality is 3–6% in high-risk patients with multiple predictors of sudden death or in patients with LVOT obstruction, which is predictive of HF-related death.10 The gradient is strongly associated with symptom progression, progressive HF, and cardiac death secondary to HF and stroke (AF).11–13 In fact, in observational studies, patients with obstructive HCM had a higher mortality than patients with non-obstructive HCM or operated obstructive HCM.11,12 This is particularly true for patients with severe resting gradient (>100 mmHg, even if asymptomatic), symptoms (NYHA II or III–IV), or functional limitation.13,14 A gradient <100 mmHg without symptoms and with a normal functional capacity (>85% of predicted METs) does not impair long-term survival.13 While LVOT obstruction is associated with HF-related death, the specific relation of obstruction to sudden cardiac death (SCD) is significant but weak. The positive predictive value for sudden death is low. A large cohort analysis has shown that there are three modes of death in HCM: SCD (~50%, age 45 ± 20), progressive HF (~36%, age 56 ± 19), and AF-related stroke. SCD, while a relatively more common cause of death in young patients <50 years old, actually has a similar yearly incidence in the older population; neither sudden nor heart-failure-related death showed a statistically significant, disproportionate age distribution.15 Most patients with HCM or HOCM are asymptomatic. Dyspnea and HF may result from LVOT obstruction and/or the small LV cavity with severely reduced diastolic filling. Angina may result from increased demands and from the elevated LVEDP, which impairs coronary microcirculatory flow; myocardial bridging is also common and may contribute to ischemia. Severe functional limitation (class III or IV) is uncommon but may eventually develop in up to 45% of patients with LVOT obstruction, over the course of 10-year follow-up.11 Conversely, up to 23% of patients may have a paradoxical reduction of gradient with exercise, which partly explains how some patients are asymptomatic.16 Two types of syncope must be distinguished: (i) exertional and (ii) post-exertional. Exertional syncope is more ominous and is secondary to arrhythmia (e.g., VT or AF) or dynamic LVOT obstruction that worsens with exertion. Conversely, in the post-exertional phase, the reduced peripheral venous pumping reduces venous return to the hypercontractile LV. This increases LVOT obstruction and may lead to syncope, but may also activate the myocardial C receptors of the small hypercontractile cavity, leading to a vasovagal syncope. HOCM is sensitive to the post-exertional preload reduction and is prone to vasovagal syncope in light of the small, hypercontractile LV cavity. Unfortunately, ~70% of patients who die suddenly have no or only mild symptoms prior to SCD, and thus SCD is often the first manifestation in patients who die suddenly. SCD often occurs at rest or with mild activities, but 15% of SCDs occur during moderate or heavy activity (relatively more so in athletes).15 ECG shows LVH voltage with a strain pattern, and/or deep T-wave inversion in leads V2–V6 even without LVH voltage. Prominent septal depolarization may lead to large Q waves in the lateral and inferior leads (pseudoinfarct pattern). Approximately 10% of HCM patients have a normal ECG, which is a limitation of pre-athletic ECG screening. Table 7.1 Exam findings in HOCM versus AS. a MR murmur (SAM) may also be heard with HOCM: blowing, holosystolic murmur at the apex (while HOCM murmur is best heard at the LLSB). This MR murmur is also worse with Valsalva. The two murmurs are heard at two different locations and are both dynamic. In the presence of a gradient between the LV and aorta and if HOCM is suspected, use an end-hole catheter, rather than a multihole catheter, and slowly pull back across the LVOT to localize the site of pressure drop. In addition to the subaortic pressure gradient, the aortic and LV pressure tracings are characterized by the following (Figure 7.4): Beside the often asymmetric LV hypertrophy, the obstructive form of HCM is characterized by SAM. SAM is seen on the parasternal long-axis view and on the M-mode of the mitral valve (Figures 7.2, 7.3). The greater the degree and duration of mitral–septal contact (e.g., > 30% of systole), the more severe the obstruction. In addition, M-mode of the aortic valve shows mid-systolic closure due to the mid-systolic obstruction. LA enlargement is universal in HCM (a normal LA size makes HCM unlikely). Figure 7.4 HOCM hemodynamics. Note the early aortic pressure peaking (blue vertical arrow), the late LV pressure peaking (horizontal arrow), and the late gradient (gray area). The aortic pressure peaks in the first 80 ms of systole; then, LVOT obstruction worsens, the LV pressure tracing ”bends” then peaks in mid- to late systole while the aortic systolic pressure adopts a “dome” appearance (LV pressure bend, black arrowhead). This contrasts with AS, where the aortic pressure bends and peaks late while the LV pressure peaks early. As opposed to AS, the mean gradient in HOCM does not characterize the obstruction well, as it integrates the unobstructed early part of systole and under-represents the LVOT obstruction. As opposed to AS, the peak-to-peak gradient approximates the peak instantaneous gradient in HOCM, and both those gradients are used to classify the severity of HOCM (≠ AS, where mean gradient is used). Figure 7.5 Brockenbrough phenomenon after a premature beat in HOCM. Note the increase in pressure gradient (interrupted lines) but the reduction in aortic pulse pressure (double arrows) after a pause in HOCM, vs. the increase in pressure gradient with an increase in aortic pulse pressure in AS. Note the “spike and dome” appearance of the aortic pressure in HOCM, which becomes more pronounced with worsening obstruction (after the pause). Pulsed-wave Doppler interrogation reveals that the velocity is increased across one point in the LVOT, but is normal (~1 m/s) or low in the LV body and distally across the aortic valve. However, the velocity may also increase in the LV body when hypertrophy is generalized with cavity obliteration, even if the obstruction is mainly at the LVOT level. The LVOT gradient is late peaking, with a “dagger” shape on spectral Doppler. It is dynamic and may be unveiled or worsened by Valsalva maneuver, which should be performed in all cases of HCM (Figure 7.6). Aliasing typically occurs across the point of LVOT obstruction rather than the aortic valve. After localizing the site of obstruction with pulsed-wave Doppler, continuous-wave Doppler is required to capture the actual velocity. Cardiac MRI may be used to further delineate the LV geometry and thickness and mitral geometry when echo is inconclusive (class I recommendation). Figure 7.6 LVOT velocity in HOCM: late-peaking dagger-shape LVOT velocity (arrows). This is opposed to the parabolic, symmetrical AS Doppler. Occasionally, an older patient may have both AS and HOCM. The continuous-wave Doppler will show two superimposed but distinct ejection envelopes (e.g., AS envelope within the HOCM envelope). Note the notch in early systole, before the LVOT envelope (stars). This notch corresponds to MR and is characteristic of LVOT interrogation in HOCM. In fact, in HOCM, MR is frequently captured on LVOT interrogation, as the mitral flow is in close proximity to the LVOT. Also, LVOT may be captured on MR interrogation. Patients without any gradient at rest may develop a significant gradient with maneuvers. The gradient increases with decreased preload (Valsalva maneuver, hypovolemia, nitroglycerin), decreased afterload (vasodilators), or increased inotropism (exercise, inotropic drugs such as dobutamine). Each of these changes results in closer approximation of the ventricular septum and anterior mitral leaflet during systole. For instance, a reduction in preload or afterload reduces LV volume and the high LV end-systolic pressure that holds the LVOT walls apart. Accordingly, the following circumstances affect the gradient: (i) gradient may rise with faster heart rates if contractility increases; (ii) gradient rises when atrial systole is lost, as in AF, as a result of reduced diastolic filling (preload); (iii) gradient may vary with respiration, particularly deep breathing: inspiration increases LV afterload and reduces the gradient, causing aortic pressure to rise (=“reverse pulse paradoxus”). While dobutamine increases the intraventricular gradient in patients with HOCM, dobutamine also induces a significant gradient in up to 20% of patients undergoing dobutamine echocardiography without suspected HOCM or even without LV hypertrophy.17,18 Dobutamine-induced gradient does not necessarily imply exertional gradient and should not be used to diagnose HOCM. In fact, exercise increases myocardial contractility but also preload, which reduces cavity obliteration and the potential for intracavitary obstruction; dobutamine increases myocardial contractility but does not increase preload, and thus more readily creates intracavitary obstruction even in the absence of HOCM. Physiological maneuvers rather than pharmacological interventions should be used to assess provocable gradient (exercise, Valsalva). Valsalva elicits gradients in only 50% of patients with exertional gradients. Thus, in a patient with exertional symptoms, exercise echo is warranted for gradient provocation if Valsalva is negative. Genetic testing identifies definite pathogenic mutations in only 60–70% of HCM cases. While the genes affected in HCM are known, the actual nucleotides affected vary widely; some sequences represent definite pathogenic mutations of the gene, while others may represent normal variants. Therefore, a positive test definitely establishes the HCM genotype, but a negative test is unhelpful. Genetic testing of an index patient is indicated for family screening purposes. If the patient tests positive for a definite mutation, first-degree family members should be screened for that same mutation. The absence of this mutation excludes the risk of HCM occurrence in these relatives and is reassuring. A positive genotype with a negative phenotype in a family member indicates a considerable risk of developing HCM; routine ECG and echo follow-up is performed throughout life. The risk of SCD is unclear, and decisions about athletic activities are individualized. Short of genetic testing, first-degree relatives of HCM patients should undergo yearly ECG and echocardiograms starting in early adolescence and until the age of 21.19 Approximately 25% of those patients will develop HCM. Afterwards, they need to be screened every 5 years for the late development of HCM (more frequent interval in case of athletic activity or family history of SCD). The differential diagnosis of dynamic LVOT obstruction includes the following:
7
Hypertrophic Cardiomyopathy
I. Definition and features of HCM
A. Definition
B. Asymmetry
C. LVOT obstruction
D. Causes of MR in HOCM; mitral valve abnormalities in HOCM
E. Less common forms of HCM
II. Natural history and mortality
III. Symptoms and ECG
HOCMa
AS
Quality
Harsh, crescendo–decrescendo mid-systolic murmur
Harsh, crescendo-decrescendo mid-systolic murmur
Location
LLSB
RUSB
Radiation
Apex/axilla, not carotids
Carotids
Carotid pulse
Brisk, double-peaked (bisferiens)
Slow, small amplitude
Dynamic with maneuvers (Valsalva, handgrip, standing)
++++
+ (changes are not usually audible)
Apical impulse
Enlarged, triple ripple (systolic ejection, systolic obstruction, and S4)
Enlarged, single impulse
IV. Exam (see Table 7.1)
V. Invasive hemodynamic findings
VI. Echocardiographic findings
VII. Provocative maneuvers
VIII. Genetic testing for diagnosis; screening of first-degree relatives
IX. Differential diagnosis of LVOT obstruction
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