Echocardiography in patients with hypertrophic cardiomyopathy: usefulness of old and new techniques in the diagnosis and pathophysiological assessment

HCM may be initially suspected because of an heart murmur, positive family history, new symptoms or abnormal ECG pattern showing LV hypertrophy and abnormal Q waves. Thereafter an echocardiogram is usually performed.

Currently, using short-axis view the left ventricle is divided in 4 LV wall segments: anterior and posterior septum and posterior and lateral wall (Figure 2, left panel) [4]. Segments are visualized at mitral and papillary level, whereas the possible extension to the apex is visualized by 4 chamber view (Figure 2, right panel). Classical LV hypertrophy cut-off suggestive of HCM in the general adult population is 15 mm [15]. Usually the pattern of LV hypertrophy is asymmetrical, with the anterior septum involved in the majority of cases being also the site of the maximal LV hypertrophy in most patients (Figure 3). In almost 40% of patients, LV hypertrophy involves two segments, whereas the concentric pattern or hypertrophy confined to the apex are particularly uncommon in Western countries (1% each) [16]. Recently, it has been demonstrated [17] that mutations in the alpha-cardiac actin gene can express apical HCM or LV non compaction or septal defects. Nevertheless, LV non compaction has to be differentiated from the apical form of HCM (Figure 4).

The heterogeneous distribution of hypertrophy in HCM results in a distortion of internal LV shape allowing algorithms, generally used to measure LV mass, not applicable in this disease. As a consequence, several echocardiographic indexes have been developed to measure the distribution and the extent of LV hypertrophy. Wigle et al [18] proposed a points score system which takes into account the degree of septal thickness, starting from a value of 15 mm, and the extension of hypertrophy up to the point of the apex. In order to calculate this score, the apical 4- chamber view is used to determine the extent of septal involvement, and the parasternal short-axis view at level of the mitral valve leaflet tips to determine the anterolateral wall involvement (Figure 5). Also, Spirito et al [15] have developed a system for assessing the magnitude of hypertrophy using the parasternal long and short-axis views and apical views (Figure 5). The overall extent of hypertrophy is defined as mild if only one LV segment is involved, moderate if two segments are involved and severe if three or more segments are involved [15] (Figure 5). Moreover, an index of hypertrophy, the Spirito-Maron index, is obtained by adding the maximal wall thickness of each LV segments. The most clinical important method is the measurement of the maximal wall thickness (MWT) at any LV level [19] (Figure 5). Extreme wall thickness, i.e. ≥ 30 mm, which can be detected at any site of LV wall, is observed less commonly in older than in younger patients, probably because of sudden death (SD) at a young age and/or of structural remodeling with wall thinning increasing with age. Spirito et al [20] showed that a maximum thickness of 30 mm or more, present in approximately 10% of HCM patients, resulted in a substantial long-term risk. However, Elliot et al [21] suggested that extreme hypertrophy is a predictor of SD only when associated with other risk factors such as unexplained syncope, family history of premature SCDs, non-sustained ventricular tachycardia at at Holter-ECG, or an abnormal blood pressure response during exercise. Furthermore, Olivotto et al [22] in a community-based population with HCM reported, during 12-year follow-up, association between maximum LV thickness and SD only in patients diagnosed at a very young age.

The degree of LV hypertrophy varies throughout life. In fact, although the gross phenotypic expression and clinical profile of HCM may occasionally be identified in infants and young children, marked LV hypertrophy is rarely documented during the first years of life [23]. Conversely, rapid changes in LV morphology often occur during adolescence and are frequently delayed completely until the second decade of life, when LV wall thickness may increase rapidly.

Genetic studies among large families demonstrated that morphological LV hypertrophy reaches a plateau at the third decade of life in β-myosin heavy chain and in α-tropomyosin mutations, whereas it increases continuously thought life in cardiac myosin binding protein C mutations [24]. The clinical implication of such an observation is that, in the contest of family screening, repeat echocardiogram to identify LV hypertrophy at yearly intervals is reasonable during adolescence, whereas repeat imaging is considered for adults at longer time intervals of 5 years. All myocardial segments, and not only the interventricular septum, should be carefully examined for screening purposes. In a recent study where genotyping was the gold standard, the Spirito-Maron hypertrophy score was highly specific with a better sensitivity than MWT [25].

Although LV remodeling in children is characterized by progression of hypertrophy, the changes in cardiac morphology observed in some adults with HCM occur in the context of development of systolic dysfunction (defined as LV ejection fraction <50%) associated or not to LV wall thinning [26] (Figure 6). This unfavorable evolution in the natural history of HCM usually develops during midlife in about 4% of patients [27]. This phase defined end stage (ES) HCM is a cause of progressive heart failure and is characterized by substantial cardiac remodeling and gradual evolution from the typical hypertrophied, non-dilated, and hyper-dynamic state to one of systolic dysfunction. ES diagnosis is primarily dependent on ejection fraction <50%, and ES commonly does not present as a dilated cardiomyopathy, with only almost 50% of patients showing associated LV cavity enlargement or regression in wall thickness; a small proportion of ES patients even demonstrate persistent marked hypertrophy with non-dilated left ventricle [27]. Clinical course is variable but generally unfavorable, and vigilant follow-up are required for timely identification of transition to ES, in order to establish appropriate pharmacological treatment for systolic pump failure, implantable defibrillator for sudden death prevention, heart transplantation.

Cross-sectional echocardiographic analyses of large HCM patient populations encompassing a broad age spectrum [28, 29] have documented morphologic differences between youthful and older patients indicating that gradual LV remodeling involving some degree of wall thinning may occur slowly over decades and may be an obligatory pathway in the natural history of HCM [28]

At opposite site, there is evidence of high degree of hypertrophy suggestive of HCM in elderly patients with and without history of arterial hypertension [30, 31]. In these patients genetic and family screening are recommended, although technique such as Tissue Doppler Imaging (TDI) and/or strain rate imaging may help in the differential diagnosis as reported below [32].

Finally, among the spectrum of sarcomeric contractile protein disease, idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations [33].

Echocardiography can visualize thickened LV walls with high sensibility and specificity, however it cannot distinguish conditions based on myocyte hypertrophy from those in which LV mass and wall thickness are increased by interstitial infiltration or intracellular accumulation of metabolic substrates. Cardiac magnetic resonance (MRI) may help into diagnostic iter (see below), moreover the final diagnosis is given only in some specific conditions by myocardial biopsy, and in particular is not indicated for the final diagnosis of HCM [34, 35]. On the other hands, it is not reasonable to investigate for each entity capable of induce increased wall thickness because of anamnestic, clinical and instrumental data that serve to orient the diagnosis before the echocardiographic study.

In the contest of genetic disease, thickening of LV walls can results also by mutations in non sarcomeric proteins involving or the gene encoding the γ-2-regulatory subunit of the AMP-activated protein kinase (PRKAG2), or the gene encoding lysosome-associated membrane protein 2 (LAMP-2), resulting in Danon-type storage disease with clinical manifestations limited largely to the heart (usually with massive degrees of LV hypertrophy and ventricular pre-excitation) [9] (Figure 7). Overall these condition are X-linked, and, thus, important clinical clues are male gender and young age.

Anderson-Fabry disease is a relatively frequent cause of idiopathic LV hypertrophy. It is a X-linked lysosomal storage disorder caused by α-galactosidase mutations and it is characterized clinically by widespread variety of signs and symptoms. Cardiac findings include LV hypertrophy, showing a symmetrical pattern in the majority of cases, mild diastolic dysfunction and preserved LV ejection fraction as well as no LV outflow tract obstruction (LVOTG) (Figure 8). The use of a binary appearance at echocardiography of LV endocardial border has been questioned in that is not a sensitive marker and it can not be routinely used to differentiate Anderson-Fabry disease from HCM [7, 8]. Symptomatic cardiac involvement usually occurs in most affected males, whereas female carriers present with minimal or no symptoms. Retrospective studies found a prevalence of Anderson-Fabry disease in 4-6% of patients previously classified as HCM, suggesting that the disease should be suspected in male patients with concentric LV hypertrophy and no family history of HCM or with inheritance consistent with X-linked disease [36].

Mitochondrial disorders result from abnormalities in mitochondrial DNA and function; mitochondrial DNA is inherited maternally, and most of these disorders are transmitted from mother to children of both sexes. In some mitochondrial disorders, LV concentric hypertrophy is present as well dilated cardiomyopathy, which probably represents a progression from the hypertrophic form. In most patients, conduction abnormalities are present [37] (Figure 9).

Involvement of the heart is a common finding and is the most frequent cause of death in amyloidosis; cardiac amyloidosis occurs more commonly in men than in women, and it is rare before the age of 40 years. The onset of clinical cardiac disease usually occurs late in life. Echocardiography is characterized in the majority of cases by symmetric LV hypertrophy, dilated atria and pericardial effusion (Figure 10). In some case the degree and the distribution of hypertrophy may resemble HCM, however LV hypertrophy together with the evidence of low voltage at electrocardiogram help in the differential diagnosis with pericardial effusion and with HCM [38].

One of the most discussed issue is how to role out HCM in athletes. Diagnosis of HCM in athletes is important, given the high propensity to sudden cardiac death in HCM patients engaging in competitive sports as well as other physically intense activity [39]. Although in Italy the ECG, which is routinely performed in competitive athletes, has dramatically reduced the incidence of sudden death due to the identification of diseases such as HCM [40], sometimes the diagnosis can be still particularly challenging in athletes with an advanced degree of physiologic LV hypertrophy. Cardiac hypertrophic response to training is different between sports [41], between individuals of the same race undergoing the same training [42], and is different between races [43]; thus, there is a very huge variability in LV hypertrophy in athletes, which sometimes is suggestive of HCM. Helpful clues include the presence of wall thickness >12 mm in the presence of a non-dilated LV in HCM, because HCM patients usually have normal or reduced LV dimensions and no cavity dilatation (>55 mm is common in athletes), except with disease progression and systolic dysfunction. HCM patients have abnormal myocardial function as detected by TDI, including mitral annulus velocities or strain rate [44]. In equivocal cases, it is reasonable to recommend stopping exercise with repeat imaging later, when one would expect regression of physiologic but not pathologic LV hypertrophy [44, 45].

In Figure 11 we suggest a clinical and echocardiographic method to approach patients with unexplained LV hypertrophy.

Right ventricular hypertrophy is diagnosed when two or more right ventricular segments are hypertrophied and when at least two right ventricular wall measurements exceed two standard deviations from the mean recorded in normal subjects. Using these criterions McKenna et al [46] reported right ventricular hypertrophy in 44% of 73 patients with HCM. More recently, Maron at al found [47] in 46 HCM patients studied by cardiac MRI, that right ventricular mass was increased in the majority of them. To date, the clinical and prognostic significance of right ventricular hypertrophy is not known.

Although SAM is the most frequent mechanism of LVOTG, obstruction can occur at mid-ventricular level or at multiple levels in the same patient and is variable with time. Continuous Doppler will give informations about the degree of obstruction (see later) whereas by pulse wave Doppler LV mapping will be performed to determine the site of obstruction. Mid-ventricular obstruction has been diagnosed by the typical angiographic feature of hourglass appearance of the left ventricle with mid-ventricular obliteration and apical chamber that is variable in size and contractility. Echocardiography has the same potential to identify this haemodynamic type of HCM (Figure 12). Patients with mid-ventricular obstruction are at high risk to develop segmental, like apical aneurysm, or diffuse LV wall motion abnormalities [48]. Moreover, structural abnormalities of the mitral valve, such as increased mitral valve area and abnormal direct insertion of papillary muscles into anterior mitral leaflet (Figure 13) can be detected by echocardiography orienting treatments' strategies.

LA volume measured by two-dimensional echocardiography has some clinical and prognostic implications. LA remodeling, measured by LA volume, relates directly with exercise tolerance as demonstrated by Sachdev et al [49] in patients without LVOTG either at rest and during provocation, suggesting that this parameter may serve as a surrogate marker of chronic diastolic burden. Moreover, patients with normal LA volume which show dilatation during follow-up, i.e. >3 ml/year, have a worse outcome than patients with normal and stable LA volume during follow-up and similar to that of patients with LA dilation at baseline [50].

Evaluation of the presence and degree of mitral regurgitation is performed by color Doppler echocardiography. Mitral regurgitation occurs in almost all patients with obstructive HCM as a consequence of SAM which induces abnormal mitral leaflet coaptation and may be an important cause of dyspnea. When additional mitral valve abnormalities other than SAM are not observed, a direct relation between the pressure gradient and the severity of MR is evident [51]. The direction of the mitral regurgitation jet is useful in identifying patients with independent mitral disease. In fact SAM induces a mitral regurgitation jet directed posteriorly, whereas in presence of a intrinsic mitral valve disease due to annular, papillary or leaflet disease, patients with obstruction and mitral regurgitation can show a systolic mitral anterior directed jet [51].

Approximately 25% of patients with HCM have a significant resting pressure gradient, i.e. ≥30 mmHg, between the body and LV outflow tract. This is nearly always accompanied by SAM. Continuous wave Doppler is used to determine peak LVOTG with caution exercised to exclude the mitral regurgitation jet [52] (Figure 14). This latter differentiation may be difficult especially in patients with mitral regurgitation jet directed anteriorly. In these cases it is of help the M-mode echocardiographic evaluation of SAM.

It is well recognized that some patients without outflow obstruction at rest have gradients that can be provoked by physiological and pharmacological interventions that diminish LV end-diastolic volume or augment LV contractility. The term labile obstruction has been used to describe the spontaneous appearance and disappearance of obstruction and latent obstruction to describe gradients that only appear with provocation. A number of methods can provoke obstruction in the echocardiography laboratory, including Valsalva maneuver, amyl nitrite, and dobutamine. However, these methods are not standardized and can underestimate the degree of obstruction such as Valsalva maneuver or have low specificity such as dobutamine. Exercise is a physiologic means of provoking latent LVOTG. Over 50% of HCM patients without significant outflow tract obstruction at rest will demonstrate outflow gradients over 30 mmHg with exercise [53, 54]. Although supine bike exercise is more conducive to acquiring multiple haemodynamic data sets, this position increases venous return and might decrease the likelihood and extent of LVOTG. Accordingly, upright exercise, which has the greatest resemblance to daily physiologic activities, should be used.

Right ventricular outflow tract obstruction may coexist with LVOTG in a minority of patients with massive septal hypertrophy and occasionally it is isolated [55].

Figure 15 shows the echo findings which are strong predictors of prognosis in patients with HCM.

Pulsed Doppler at mitral and pulmonary level is used to assess the presence and the degree of diastolic dysfunction. Almost all patients with HCM have some degree of LV diastolic dysfunction. Figure 16 reports a scheme of the molecular, morphological and haemodynamic factors which may contribute to diastolic dysfunction in HCM. These complex mechanisms determine that all phases of diastole are altered. Isovolumic relaxation is slowed and prolonged, the rate of rapid filling is diminished, atrial contribution to filling is increased as well as LV chamber stiffness [56]. The importance of diastolic dysfunction in HCM has led to an extensive search for accurate, noninvasive methods of quantifying its severity. When LV end-diastolic pressure is considered, the echo pulsed Doppler parameter with a good relationship is represented by the difference in duration between the atrial contraction wave at mitral and pulmonary level [57]. Lombardi et al [58] demonstrated that as the difference in duration worsens myocardial collagen synthesis prevails over degradation; moreover, an echocardiography index of myocardial fibrosis, i.e. diastolic back scatter, increases [59], suggesting a strong interplay between diastolic function and myocardial fibrosis.

New technologies have been employed in the patho-physiological assessment, in preclinical diagnosis, in differential diagnosis, and in risk stratification of HCM.

The diagnosis of HCM is most easily and reliably established by clinical and instrumental examination in the majority of affected adult patients. Thus, in patients with certain clinical diagnosis, genetic testing represents only a diagnostic confirmation. Nevertheless, molecular studies have the potential to enhance diagnostic reliability in HCM and can play an important role in resolving ambiguous diagnoses [82]. Moreover, in selected pedigrees genetic testing, has led to the identification of increasing numbers of children and adults with a preclinical diagnosis of HCM. These individuals have a disease-causing genetic mutation but no clinical or phenotypic manifestations of HCM. At present, there is no available evidence to justify precluding such genotype-positive, phenotype-negative individuals from most employment opportunities or life activities; however, a family history of frequent HCM-related death or the documentation of a particularly malignant genotype may justify efforts at risk stratification and possible restriction from competitive sports. Such a clinical scenario suggest that it is extremely important that family members receive careful counseling both before and after testing [83].