Echocardiography in patients with hypertrophic cardiomyopathy: usefulness of old and new techniques in the diagnosis and pathophysiological assessment
- Maria-Angela Losi1Email author,
- Stefano Nistri2,
- Maurizio Galderisi3,
- Sandro Betocchi1,
- Franco Cecchi4,
- Iacopo Olivotto4,
- Eustachio Agricola5,
- Piercarlo Ballo6,
- Simona Buralli7,
- Antonello D'Andrea8,
- Arcangelo D'Errico3,
- Donato Mele9,
- Susanna Sciomer10,
- Sergio Mondillo10, 11 and
- the Working Group of Echocardiography of the Italian Society of Cardiology
© Losi et al; licensee BioMed Central Ltd. 2010
Received: 27 January 2010
Accepted: 17 March 2010
Published: 17 March 2010
Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiomyopathy. The identification of patients with HCM is sometimes still a challenge. Moreover, the pathophysiology of the disease is complex because of left ventricular hyper-contractile state, diastolic dysfunction, ischemia and obstruction which can be coexistent in the same patient. In this review, we discuss the current and emerging echocardiographic methodology that can help physicians in the correct diagnostic and pathophysiological assessment of patients with HCM.
Hypertrophic cardiomyopathy (HCM) is clinically defined in presence of left ventricular (LV) hypertrophy in the absence of hypertension and valve disease. LV hypertrophy without cardiovascular causes occurs in approximately 1:500 of the general population [1–3]. This incidence includes all kinds of hypertrophy not necessarily HCM, which is a familial disease with an autosomal dominant pattern of inheritance caused by mutations in genes encoding for sarcomeric proteins resulting usually in an asymmetrical pattern of LV hypertrophy. Echocardiography plays a pivotal role in detecting the disease and understanding its pathophysiology. In this review, we discuss the current and emerging echocardiographic methodology that can help physician in the correct diagnosis and pathophysiological assessment of patients with HCM.
Echocardiography and Diagnosis
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.
The movement of mitral valve is easily visualized by M-Mode and its anterior motion during systole, together with asymmetrical septal hypertrophy, was initially thought to be pathognomonic of HCM. However, these findings may be present in other forms of secondary and primary hypertrophy, like chronic systemic and reno-vascular hypertension , Fabry's disease [7, 8], glicogenosis , Friedreich ataxia , etc.
Left atrial (LA) diameter is usually increased in patients with HCM because of obstruction and/or diastolic dysfunction. LA diameter gives informations about the risk of atrial fibrillation, of heart failure development and of cardiac mortality  which is particularly high in patients with a LA diameter > 48 mm. Finally, LA fractional shortening, evaluated as ([maximal diameter-minimum diameter]/maximal diameter*100), is an estimate of end-diastolic pressure in HCM ; this parameter is directly related to exercise tolerance , and its reduction (i.e.<16%) represents an independent risk factor for atrial fibrillation development .
This technique by visualizing the whole heart has come the recognition that LV hypertrophy is most often asymmetrical and it can be confined in specific LV segments such as the apex.
LV hypertrophy and function
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 . 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 . 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 .
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 
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 .
Finally, among the spectrum of sarcomeric contractile protein disease, idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations .
LV hypertrophy in other forms of genetic diseases
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.
Athletic heart and HCM
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 . 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 , 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 , between individuals of the same race undergoing the same training , and is different between races ; 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 . 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].
Right ventricular 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  reported right ventricular hypertrophy in 44% of 73 patients with HCM. More recently, Maron at al found  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.
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  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 .
Each Doppler technique offers relevant contribution in the analysis of patients with HCM .
Color Doppler echocardiography
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 . 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 .
Continuous Doppler echocardiography. Exercise echocardiography
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 .
New echocardiographic technologies
New technologies have been employed in the patho-physiological assessment, in preclinical diagnosis, in differential diagnosis, and in risk stratification of HCM.
Contrast echocardiography currently is used to enhance endocardial definition, Doppler signals, and to evaluate myocardial perfusion during percutaneous transluminal septal myocardial ablation (PTSMA). PTSMA is a catheter interventional treatment which involves the introduction of absolute alcohol into a septal perforator branch of the left anterior descending coronary artery to produce a myocardial infarction within the proximal ventricular septum. The aim is similar to that of myotomy-myectomy, i.e. reducing the basal septal thickness and excursion enlarging the LV outflow tract and, thereby, lessening the SAM of the mitral valve and mitral regurgitation. The introduction of the echo contrast has proved to reduced the side effects of the technique: it selects the appropriate septal perforator branch determining the precise area of septum targeted for alcohol ablation and evaluates whether selected septal perforator also perfuses other distant and unwanted areas of LV or right ventricular myocardium or papillary muscles .
A potential role for contrast enhancement in the diagnosis of apical HCM has been demonstrated , although systematic studies have not be yet performed.
Tissue Doppler Imaging
Given the complex interplay of factors causing diastolic dysfunction in HCM, it should not be surprising that no single non-invasive measure has been definitively validated. Nagueh et al  suggested that the ratio of early transmitral (E) to tissue Doppler early diastolic (e') velocities of the lateral mitral annulus accurately quantified LV pressures, in particular the LV pressure before atrial contraction, an E/e' ≥10 showed the best sensitivity and specificity for identifying LV pre-A pressure > 15 mmHg. However, that ratio shows only a modest correlation when related to mean left atrial (LA) pressure, and, moreover, the predictive accuracy of the E/e' ratio for estimation of mean LA pressure in an individual patient was modest . However, in some study this parameter identifies patients with low exercise capacity [63, 64].
TDI has been investigated in the preclinical diagnosis of HCM. Studies from transgenic animal models revealed some abnormal myocardial function at a time preceding the development of LV hypertrophy, firstly due to alterations in Ca++ sensitivity  which probably induce low TDI velocities at annular mitral level. Although some reports have provided encouraging results [66, 67], additional data from a larger number of subjects are needed to determine TDI velocity values that provide the highest diagnostic accuracy.
Strain rate imaging
Patients with HCM may show regional differences in wall motion at rest . Betocchi et al  demonstrated that LV regions with less pronounced myopathic process are those with normal stiffness and with supernormal wall motion. In contrast, the stiffer septum shows reduced wall motion compared with adjacent regions. Other mechanisms may explain regional asynergy such as anatomic nonuniformity, altered calcium handling, subendocardial ischemia and altered glucose metabolism.
Strain rate imaging has been shown to measure accurately LV torsion . LV untwisting is linked temporally with early diastolic base-to-apex pressure gradients, enhanced by exercise, which may assist efficient LV filling. This effect appears blunted during exercise in HCM , particularly in patients with the obstructive form .
A frequent clinical issue is to establish the final diagnosis in patients with high degree of LV hypertrophy and arterial hypertension; recently, more severely reduced systolic compression (by strain Doppler echocardiography) along with asymmetric LV hypertrophy readily identified HCM patients from those with hypertension . Receiver-operator characteristic curve analysis identified the optimal cut-off value of strain, i.e. systolic longitudinal strain by 4 and 2 chamber views, for discrimination between HCM and hypertensive LV hypertrophy, as -10.6%; this value was associated with a sensitivity, specificity, and predictive accuracy of 85, 100, and 91.2%, respectively. Similarly, an intraventricular septal/posterior wall thicknesses ratio of 1.3 was associated with a sensitivity of 65%, specificity of 100%, and predictive accuracy of 79.4%. A discriminant function test revealed that a discriminant score (Z) defined by the following equation yielded the highest discriminant probability of 96.1%: Z = -1.7044 + (15.2316 × IVST/PWT) + (1.52687 × strain), where Z > 0 indicates a diagnosis of HCM and Z < 0 indicates a diagnosis of hypertensive LV hypertrophy.
Strain rate imaging has been involved in the differentiation of HCM from cardiac amyloidosis in one study where, however, patients with amyloidosis were in the late stage characterized by low ejection fraction. This suggests that the early differentiation of amyloidosis versus HCM using strain (i.e., before the development of systolic dysfunction) may be still difficult .
Real time 3-dimensional echocardiography
Real time 3-dimensional echocardiography has been applied to determine LV mass, but there is a paucity of data about its accuracy in HCM. To date, MWT remains the best and the more simple and important measurement that should be reported, because it can predict sudden cardiac death in this population.
Coronary flow reserve
Stress echocardiography with dypiridamole has been used to test prognostic role of electrographic signs of inducible ischemia in patients with HCM. In one paper , ECG signs of myocardial ischemia elicited by dipyridamole were frequent identify patients at higher risk of cardiac major and minor events, suggesting a important pathogenetic role of inducible myocardial ischemia in determining adverse cardiac events in these patients.
Quantitative evaluation of coronary flow reserve studied by positron emission tomography is a strong predictor of progression to severe symptoms and to ES HCM . An estimate of coronary flow reserve can be obtained in the echo-lab by the simple transthoracic Doppler echocardiographic approach of the mid-distal left anterior descending artery and recently its prognostic role has been tested in a population of patients with HCM. Cortigiani et al , found that patients with reduced coronary flow reserve (≤2) have a worse prognosis than patients with normal values (>2). Clinical events recorded during follow-up were death, nonfatal myocardial infarction (defined by typical symptoms, increased cardiac enzyme, and/or electrocardiographic changes), cardioverter- defibrillator implantation, hospitalization for heart failure or unstable angina, syncope, and paroxysmal or chronic atrial fibrillation. Authors found that this coronary flow reserve was a strong and independent predictor of outcome in HCM patients.
MRI is an important imaging technique with an expanding role in the contemporary evaluation of patients with HCM; it provides complete LV reconstruction and a precise definition of the distribution and pattern of hypertrophy . This is particularly useful in patients without a clear LV anatomic characterization by echocardiography. Measurements of MWT by echocardiography and by MRI are strictly related whereas MWT shows weak relationship when related to LV mass [79, 80].
In patients highly suspected to have HCM, but with a negative echocardiogram for LV hypertrophy, MRI represents an additive diagnostic chance as proposed by Rickers et al; Authors found, in a population involving almost 50 patients, that MRI was capable of identifying regions of LV hypertrophy (in particular at anterolateral level) not readily recognized by echocardiography, which were solely responsible for diagnosis of the HCM phenotype in an important minority of patients . Moreover, the measure of LV mass and the characterization of abnormal substrate of fibrosis will probably provide implications of these findings in the risk stratification . Nevertheless, it must be underscored that MRI doesn't provide complete LV tissue characterization and, thus, can not be used as a non-invasive biopsy.
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 . 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 .
Two-dimensional echocardiography has been the most used, efficient and accessible technique for establishment of the diagnosis of HCM. Echocardiography can provide important information for the appropriate diagnosis and pathophysiological assessment of HCM patients. However, echocardiography alone can not differentiate different forms of unexplained LV hypertrophy. It must be underscore that its role is highlight only when is used after a complex clinical evaluation including familial and personal anamnesis, clinical examination, electrocardiogram, haemato-chemical tests.
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