The role of echocardiography for diagnosis and prognostic stratification in hypertrophic cardiomyopathy

While initially thought to be a disease limited to the myocardium, it is now well known that up to 59% of patients diagnosed with HCM have at least one abnormality of the mitral valve apparatus (MVA) as a direct effect of genetic mutations [23]. More commonly, leaflet elongation and excessive leaflet tissue are present in about 50% of patients, while other anomalies like chordal elongation, prolapse and direct insertion of the papillary muscle into the anterior leaflet are present in about 25% of cases [19]. The abnormalities also extend to the papillary muscles (PM) and may be related to their relative position (apical/anterior displacement), insertion (directly on the mitral valve) and number (duplication, bifidity)/hypertrophy [19].

Systolic anterior motion (SAM) of the mitral valve/chordae was once thought to be a very specific finding in HCM, being present in about 30–60% of the cases [24]. This theory is currently disproven, since other causes can also lead to SAM. These need to be taken into account when assessing the patient (e.g., severe HTN with small LV cavity treated aggressively, mitral valve surgical repair, severe hypovolemia, inotrope use) [18, 19].

Mitral regurgitation (MR) can be a result of MVA abnormalities, SAM (usually eccentric, posterior MR jet) and/or coexistence of mitral valve degenerative disease (usually central MR jet) [18, 19, 25].

Left ventricular ejection fraction (LVEF) is typically normal/supranormal in patients with HCM, and it only decreases in the late-stage “burnt-out” HCM in a small subset of patients (less than 15%) [17].

LVEF can remain normal in HCM because of the complex remodeling of LV structure and function. Thus, LVEF remains normal despite significant reduction in longitudinal and circumferential deformation, because of increased radial deformation in patients with increased WT and a small LV cavity [26]. Therefore, assessing myocardial deformation will better reflect LV systolic function in patients with HCM. Tissue Doppler imaging (TDI) can be used to assess mitral annular velocities and can detect subtle alteration in longitudinal function, even in segments without significant hypertrophy [27, 28]. While using TDI to assess strain and strain rate has Doppler-specific limitations (e.g., angle dependence), 2D-derived speckle tracking echocardiography (2D-STE) can provide more reproducible measurements of LV strain [29]. Typically, patients with HCM have a significant reduction in longitudinal strain (hypertrophied segments/segments with fibrosis being the most affected), even in early phases (subclinical systolic dysfunction), and a reduced LV untwisting [19, 29]. Moreover, paradoxical apical strain (systolic lengthening of apical segments) could be used to improve the diagnostic yield of echocardiography in apical HCM [30].

One of the main mechanisms of HF in patients with HCM is LV diastolic dysfunction which occurs early in the disease evolution and is due to increased LV mass and stiffness [18, 19]. Transmitral flow is usually abnormal, and early diastolic myocardial velocity (e’) is frequently decreased, even in segments not affected by hypertrophy [31]. An increase in left atrium indexed volume (LAVI), especially if there is no significant MR/history of atrial fibrillation (AF), is a good surrogate for increased LV filling pressures [32]. It should be noted that transmitral flow E/A ratio and E/e’ ratio have poor/modest correlations with LV filing pressures in patients with HCM [33]. The Valsalva maneuver can be used in patients with an impaired relaxation pattern to unmask elevated LV filling pressures, proven by an increase in A wave velocity during the maneuver [34]. Table 1 summarizes the main echocardiographic parameters that can be used for assessing LV filling pressures [35]. In the presence of normal LAVI/LV filling pressures, the diagnosis of HCM is less likely, especially in elderly patients [18].

While usually located in the LVOT, the site of obstruction can also be midventricular. A peak gradient > 30 mmHg at rest or after provocative maneuvers (Valsalva/standing/exercise) is defined as intraventricular obstruction [17]. More than two-thirds of HCM patients have significant obstruction, but in half of them, this becomes apparent only after provocation [36]. Moreover, the intraventricular gradient has a significant variability, related to changes in loading conditions and in contractility [37]. In HCM, the main cause of LVOT obstruction is MVA abnormalities associated with a steeper LV to aortic root angle, leading to SAM, while the IVS thickness plays a lesser role by narrowing the LVOT (Fig. 2) [38]. Color flow mapping and pulse-wave (PW) Doppler can be used to identify the anatomic site of obstruction, and a careful assessment of the whole LV (apex/midventricular/LVOT) should be routinely made in all patients [18, 19]. Continuous-wave (CW) Doppler is useful in measuring the peak gradient. The Doppler envelope is typically “dagger shaped” (with an end-systolic peak), or like a “lobster claw” in cases of more severe obstruction (with a midsystolic temporary drop in pressure). Care should be taken not to measure the MR jet (which is “bell-shaped”), since this will overestimate obstruction severity [19]. Resting provocative maneuvers (e.g., Valsalva, standing) are mandatory in all patients [19].

Midventricular obstruction usually occurs in patients with significant midventricular hypertrophy and small LV cavity (“hourglass shaped ventricle”), more so if PM anomalies are present. It increases the risk of apical aneurysms that in turn predispose to ventricular arrhythmias and systemic embolism (in cases of apical thrombi) [18, 19].

Exercise echocardiography (EE, by treadmill/bicycle) is recommended in all symptomatic patients with resting intraventricular gradients < 50 mmHg or in asymptomatic patients when it is relevant for their medical treatment and for further risk stratification. Exercise echocardiography is a safe and feasible investigation [1]. Beside gradient provocation, exercise echocardiography is very useful for assessing exercise tolerance/symptoms, response to therapy, MR severity, blood pressure response, myocardial ischemia and exercise-induced arrhythmias [19, 39].

Carriers of HCM gene mutations or subjects with ambiguous/negative genetic testing (30–40% of patients) who are asymptomatic and have some characteristics of HCM phenotype but do not fulfill the diagnostic criteria are considered to have subclinical HCM [40]. Even if the additional risk for SCD is very low in these patients, they should be carefully monitored with frequent echocardiograms, as opposed to HCM relatives with no abnormalities [41].

Echocardiographic findings include normal WT/borderline hypertrophy (12–14 mm), mitral valve leaflet elongation, myocardial crypts and myocardial apical trabeculations (the latter are better seen at cardiac magnetic resonance, CMR), while the LA is usually normal or only mildly dilated [19, 40]. TDI-derived myocardial velocities and 2D strain analysis can be useful since even patients with normal WT can have reduced myocardial velocities and mild segmental longitudinal dysfunction [42]. Moreover, exercise echocardiography can be performed to look for exercise-induced intraventricular gradients due to SAM, an additional finding suggestive of HCM [39].

Three-dimensional echocardiography (3DE) has some advantages over standard 2D echocardiography. It can provide better information regarding the mechanism of intraventricular obstruction, distribution of hypertrophy, LV mass and systolic function. 3DE derived LV volumes, mass and ejection fraction have a better correlation with those obtained using CMR [19]. Moreover, 3DE can be useful for the differential diagnosis with other causes of LV hypertrophy. A novel index based on the standard deviation of the segmental mass volumes called the mass dispersion index (MDI) was proven to be significantly higher in patients with HCM, irrespective of the localization of hypertrophy [43, 44].

Dyssynchronous contraction in the absence of intra/interventricular conduction defects on the ECG is common in patients with HCM, especially if they have significant LVOT obstruction or septal hypertrophy [44, 45].

Key echocardiographic features for differentiating HCM from other diseases leading to LV hypertrophy are presented in Table 2.

While in the community, most patients with HCM have a relatively good prognosis, with an estimated SCD risk of about 1% annually (compared to 0.2% in the general population), the risk can be significantly higher (over 6%/5 years) in patients presenting with more risk factors. Therefore, risk stratification is paramount to assess the need for an implantable cardioverter–defibrillator, which is the only effective treatment in reducing the SCD risk [1, 17].

Currently, there are two widely used multiparametric approaches for risk stratification, endorsed by ESC and AHA/ACC respectively, where all predictors are independently correlated with SCD. The risk model proposed by AHA/ACC is based on an international registry of 506 patients, has a very good sensitivity (SCD risk after applying the algorithm is less than 0.5%/year) and includes novel risk factors such as late gadolinium enhancement at CMR and the presence of LV apical aneurysms, beside maximal wall thickness > 30 mm, the presence of unexplained syncope, NSVT, family history of SCD and abnormal BP response to stress [17]. The main limitations are the fact that the model uses binary variables and does not include some risk modifiers [17]. The HCM SCD risk calculator proposed by the ESC is based on a multicenter cohort study of 3675 patients and provides individualized 5-year risk estimates using seven variables (age, maximum LV wall thickness, left atrial size, LVOT gradient at rest, family history of SCD, NSVT and unexplained syncope). Half of the parameters used in both models are derived from echocardiography [1].

The severity of hypertrophy assessed by maximal wall thickness (MWT) has been linked to VA, especially in younger patients. Patients with severe hypertrophy (MWT > 30 mm) have a threefold higher risk for VA. There are no data regarding the importance of ventricular mass/hypertrophy distribution and risk of VA [14, 45].

LVOT obstruction at rest increases the absolute risk of SCD from 0.9% to 1.5%. Unfortunately, the relation between severity of obstruction and SCD risk is less clear and there is low additive value in the absence of other risk factors. Moreover, LVOT gradients are highly variable [46].

LA remodeling is related to LV remodeling; therefore, an increase in LA diameter is a marker of disease severity. Currently, the relation between atrial fibrillation and SCD is still unclear. While the LA anteroposterior diameter is easy to measure, it is not ideal, since LA dilatation is not uniform, and LA diameter may underestimate the true LA size. Thus, LA volume may be a superior measure of LA size for risk stratification of patients with HCM [32]. However, more studies are needed to prove this hypothesis.

The presence of apical aneurysm increases the risk of SCD (40% patients have NSVT), with a significant prognostic value for aneurysms larger than 4 cm, and a mortality of 3.4%/year [47].

Beside well-established echocardiographic risk factors, there are novel echo parameters derived from 2D STE analysis that may provide additional insight in SCD risk stratification. In a study on more than 3000 HCM patients, abnormal GLS was associated with VA [48]. Mechanical dispersion (i.e., the standard deviation of the time from the onset of systole to maximum contraction for each of the myocardial segments, an expression of heterogeneous contraction and electrical activation) relates to the extent of fibrosis (assessed by CMR) and is an independent predictor of VA (Fig. 3) [49].

The pathophysiology of HF in HCM is multifactorial—from diastolic dysfunction due to delayed LV relaxation, decreased chamber compliance, loss of LV suction and abnormal calcium homeostasis to LVOT obstruction and myocardial ischemia secondary to the reduction in myocardial blood supply, abnormal vasomotor response and vascular remodeling. Echocardiography plays an important role both in diagnosing cardiac remodeling and LVOT obstruction and in predicting progression to HF [19]. The finding of elevated LV filling pressure has a negative prognostic impact in HCM patients [50]. Right ventricular involvement, a common finding in about 50% of the patients, increases the risk for developing HF symptoms and VA (NSVT), with a direct correlation between RV wall thickness and heart failure symptoms [21].

Intraventricular obstruction increases the myocardial load and reduces the blood supply and cardiac output. The coexistence of significant MR can also worsen the HF symptoms. In symptomatic patients, in the absence of significant obstruction at rest (< 30 mmHg), gradient provocation (by specific maneuvers or by exercise echocardiography) should be pursued. LVOT obstruction is a predictor of HF symptoms (38% patients with resting obstruction have HF symptoms, compared with 20% of patients with provocable obstruction and 10% of patients without obstruction) and HF progression irrespective of its severity, with a greater magnitude in older patients (> 60 years) [51]. Exercise tolerance, lack of contractile reserve and the presence of inducible ischemia at exercise echocardiography have independent prognostic value [52].

Myocardial deformation can bring additional prognostic information. A marked reduction in LV systolic velocity by TDI (S < 4 cm/s at the lateral site) is an independent predictor of death or hospitalization for worsening HF [50]. Moreover, abnormal LV-GLS was associated with adverse composite cardiac outcomes [48]. Significant LA dysfunction (assessed by STE) has also been shown to correlate independently with HF symptoms [53].

The prevalence of AF in HCM is about 20–30%, compared to 1% in the general population [54]. The occurrence of AF increases morbidity and mortality leading to HF and thromboembolic events. Diagnosing AF can be difficult, since most paroxysmal AF episodes are asymptomatic. LA dimensions and age are independently associated with AF, but current tools to predict AF and thromboembolism lack in sensitivity and specificity [1, 17]. The ESC guidelines recommend screening for AF with ambulatory 48 h ECG monitoring for patients with an anteroposterior LA diameter > 45 mm [1]. Unfortunately, LA diameter lacks sensitivity. Among so-called low-risk patients (with an anteroposterior LA diameter < 45 mm), the incidence of AF is between 20 and 50% [54]. LA volume and strain can further refine risk stratification for AF in these patients, being more sensitive in detecting atrial remodeling, the main substrate of AF (Fig. 4). An indexed LA volume ≥ 37 mL/m² and LA strain ≤ 23.4% were predictive for new-onset AF, with good accuracy (AUC = 0.83, and AUC = 0.78, respectively) [54]. Predictors for stroke include the presence of HF (NYHA class III/IV), age > 60 years, LVOT obstruction and AF/LA size > 45 mm (the most accurate predictors) [55].