*HCM diagnosiss and differential diagnosis: "from athlete's heart to HCM phenocopies". Inheritance, signs or symptoms of multi-organ involvement, ECG abnormalities beyond LVH criteria, routine laboratory tests, echocardiographic and CMR main findings are shown for HCM and each phenocopies.*

#### *Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

Detailed arterial hypertension history and arterial blood pressure assessment as well as clinical evaluation of relatives may be crucial in distinguishing between hypertensive heart and HCM. Moreover, a multimodality imaging approach is crucial in the differential diagnosis of HCM in hypertensive patients. Echocardiographic tissue doppler shows more impairment of diastolic function as well as lower early diastolic velocities in HCM [67, 68]. Similarly, two-dimensional (2D) strain echocardiography in HCM reveals a mid and apical short axis segments reduced radial strain as well as a reduced longitudinal strain in HCM with sarcomeric mutations [67, 68]. Moreover, myocardial fibrosis in CMR imaging as well as natriuretic peptides and troponin levels tend to be higher in HCM than in hypertensive heart [69].

#### *4.2.3 HCM phenocopies*

Significant advances and widespread availability of genetic testing at the same time have improved detection of the sarcomeric mutations that cause HCM but have also highlighted the significance of inborn errors of metabolism or metabolic storage disorders that can mimic HCM, named "HCM phenocopies" [70]. Five to ten percent of adult cases of HCM are caused by other genetic disorders including inherited metabolic and neuromuscular diseases, chromosome abnormalities, genetic syndromes as well as non-genetic disorders (e.g. TTR or AL amyloidosis) [71–74]. Whilst HCM phenocopies are relatively rare, it is crucial to distinguish these conditions at an early stage as their natural history, management, therapy and prognosis vary significantly from that of HCM with sarcomeric mutations. **Table 1** illustrates the salient features (red flags) of HCM phenocopies.

#### **4.3 Multimodality imaging in HCM**

Imaging techniques play an essential role in the evaluation of patients with HCM. A multimodality approach using ECG, echocardiography, CMR, cardiac computed tomography (CCT) and cardiac nuclear imaging provides unique information about diagnosis, staging and clinical profiles, anatomical and functional assessment, metabolic evaluation, monitoring of treatment, follow-up, prognosis and risk stratification, as well as preclinical screening and differential diagnosis (**Figure 2**).

**ECG**: is recommended at the first clinic visit in all individuals with known or suspected HCM and should be repeated whenever there is a change in symptoms in patients with an established diagnosis. It can be normal at presentation but generally shows a variable combination of LV hypertrohy (LVH), ST- and T-wave abnormalities and pathological Q-wave; ECG abnormalities that could mimicks other conditions, such as myocardial ischaemia or infarction, when interpreted together with echocardiography and CMR imaging findings, can suggest an underlying diagnosis or provide clues to the distribution of LVH and myocardial scar [75]. Moreover, since ECG abnormalities generally precede the development of LVH, periodic clinical and instrumental evaluations as well as family screening are useful even in the absence of conclusive diagnostic criteria. The frequency of arrhythmias detected during ambulatory electrocardiographic monitoring is age-related; asymptomatic non-sustained ventricular tachycardia (NSVT) occurs in 25% of adults with HCM and for this reason a 24 or 48 hour Holter ECG represents a primary test for estimate the risk of SCD [2, 76–77].

**Echocardiography**: is the central imaging technique to the diagnosis and monitoring of HCM, given that identifies and quantify LVH that generally is asymmetric and involving the interventricular septum in the basal LV segments but often extends into the lateral wall, the posterior septum and LV apex [78]. In fact, increased ventricular wall thickness can be potentially found at any location. *Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

#### **Figure 2.**

*HCM: Inheritance and multimodality imaging. Panel A shows an HCM family pedigree with a MYH7+ mutation (autosomal dominant inheritance). The father and two of his children had HCM, another child was unaffected and was excluded from further clinical testing, and one child had a pathogenic mutation without LV hypertrophy. Black symbols denote affected family members, white symbols unaffected family members, squares male family members, and circles female family members; the arrow indicates the proband. The numbers under the symbols indicate age (in years) at the time of testing. Panel B shows ECG abnormalities in HCM characterized by: Short PR-interval, high QRS voltage, ST depression followed by diffuse giant T wave inversion. Panel C: HCM with extreme asymmetrical septal hypertrophy (45 mm – Echocardiography). Panel D: Apical HCM (echocardiography). Panel E shows HOCM with significant left ventricular outflowtract obstruction (74 mmHg peak gradient at echocardiography). Panel F shows a triphasic doppler inflow velocities with restrictive pattern in addition to L wave (arrow) in HCM patients with thin myofilament associated mutation (upper side). Tissue Doppler showing severe diastolic dysfunction characterized by low e' (arrow) velocities (lower side). Panel G: Severe (24 mm) septal asymmetrical hypertrophy (arrow) in HCM (echocardiography). Panel H: Severe septal asymmetrical hypertrophy (arrow) in HCM (cardiac magnetic resonance). Panel I: HCM with fibrosis (cardiac magnetic resonance – LGE - arrow) at RV insertion points and intramural in the intraventricular septum. Panel L: HCM with diffuse and marked intramyocardial fibrosis (cardiac magnetic resonance – LGE - arrow) (Figure 3).*

Moreover, echocardiography estimates systolic and diastolic function, the presence of left ventricular outflow tract (LVOT) obstruction at rest and/or under provocative maneuvers such as Valsalva or standing, midventricular obstruction, mitral

valve abnormalities (mitral SAM, leaflets elongation with excessive tissue, dysplasia and prolapse, chordal elongation, laxity and hypermobility), atrial enlargement, or apical aneurysm [79]. Stress echocardiography can be used to detect myocardial ischemia, significant misunderstood LVOT obstruction, symptoms and blood pressure response to exercise [80].

**Cardiovascular magnetic resonance (CMR) imaging**: provides detailed information on cardiac morphology, ventricular function and myocardial tissue characteristics [81]. CMR estimate left ventricle volumes, mass, ejection fraction as well as quantification, location, type and distribution of LVH but especially the visualization and quantification of myocardial fibrosis (LGE) [80].

In detection of myocardial ischaemia CCT is useful to evaluate the presence of epicardial coronary artery disease (CAD) in patients with HCM.

**Single photon emission computed tomography/position emition tomography (SPECT/PET)** myocardial perfusion imaging (using Thallium-201 and Tc-99 m labeled tracers) is useful to evaluate the presence of coronary microvascular dysfuntion showing reversible and fixed defects, thereby suggesting ischaemia and scar, with or without epicardial CAD detecting [82]. The assessment of myocardial metabolism can be performed through PET with F-18-fluorodeoxyglucose (FDG) or C-11-acetate, since an impairment in oxidative and glucose metabolism, mainly in the hypertrophic myocardium, has been found in HCM [83]. PET imaging has also been used to assess cardiac autonomic dysfunction, given that increased local catecholamine levels due to impaired neurotransmitter re-uptake into the cardiac nerve terminals, leading to decreased myocardial beta-adrenoceptor density, has been found in HCM [84].

**Cardiopulmonary exercise testing (CPET):** provides objective information about the severity of functional limitation, mechanisms responsible for symptoms during effort and plays a central role for cardiac transplantation indication [85]. CPET may be helpful in differentiating HCM from physiological ventricular hypertrophy since maximal oxygen consumption is normal or supra-normal in athlete's heart and reduced in HCM. Moreover, CPET or conventional treadmill- or bicycle ergometry may be used in several contests: initial clinical evaluation, change in symptoms, LVOT gradient evaluation during effort, blood pressure response during exercise, detecting signs of myocardial ischemia caused by epicardial CAD and/or microvascular dysfunction [86–90].

#### **5. Clinical course and disease stanging**

HCM may be associated with a normal life expectancy and a very stable clinical course. However, about a third of patients develop heart failure (HF); in addition, 5–15% of cases show progression to either the restrictive or the dilated hypokinetic evolution of HCM, both of which may require evaluation for cardiac transplantation [91, 92]. The clinical course of HCM has been masterfully classified by Olivotto et al. into four clinical stages: non-hypertrophic, classic, adverse remodeling and overt dysfunction phenotype [93] (**Figure 3**).

**Non-hypertrophic HCM:** is characterized by the absence of LVH in individuals with HCM-causing mutations identification during systematic family screenings. This stage of the disease is more frequent in newborn or very young children, while LVH tends to manifest during the second decade of life. However, due to incomplete penetrance and age-related onset, genotype-positive individuals can develop LVH as late as the 6th or 7th decade, and a significant minority seem to never develop the disease at all [94–96]. ECG, in this contest, is a fundamental tool to identify these patients since abnormalities can usually be evident even in the absence of LVH *Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

#### **Figure 3.**

*Clinical stage and phenotypes of HCM: Prevalence, symptoms and main findings are separately shown for each stage of the disease.*

on the echocardiogram [94]. Echocardiographic abnormalities may be found and includes impaired LV relaxation, mitral valve or subvalvar abnormalities, and mild degrees of left atrial enlargement. Although not diagnostic, these abnormalities may useful to suspect HCM in the context of familiar screening or ECG abnormalities context [79–94]. CMR shows some degree of LV hypertrophy in about 16% of genotype-positive subjects with negative echocardiography. Prognosis of genotypepositive individuals in this stage is unresolved, but presumed favorable [95, 96].

**Classic HCM Phenotype:** is defined as the phase in which the hypertrophic phenotype is fully expressed and the LV is hyperdynamic (as defined by an LV-EF >65%), without extensive fibrotic changes. LVH is typically regional and asymmetrical, generally involving the basal septum and anterior wall, but can potentially involve any part of myocardial muscle such as right ventricle or papillary muscles [94–97]. Moreover, a large number of mitral valve, sub-valvar, subaortic, midventricular abnormalities, atrial remodeling, coronary myocardial bridging, coronary microvascular dysfunction, crypts and autonomic nervous system abnormalities are present in this stage of the disease [79–99]. This stage is characterized by classic features such as myocardial disarray, microvascular remodeling, and interstitial fibrosis [95–101]. Most patients experience long periods of clinical stability without symptoms and may never undergo significant degrees of adverse remodeling or disease progression during their lifetime. Life expectancy is relatively favorable, with an annual cardiovascular mortality around 1% [94–102].

**Adverse Remodeling Phenotype:** is defined as the presence of structural modifications due to increasing LV fibrosis with worsening function (LV-EF 50%–65%) associated with relatively preserved clinical and hemodynamic balance (15% to 20% of patients) [103–105]. The definition of this intermediate stage of disease progression is based on a combination of several structural and functional features including an LV-EF in the low-normal range [106], moderate to severe diastolic dysfunction [107, 108], marked atrial enlargement [109], moderate areas of LV fibrosis [94, 106–111], severe microvascular dysfunction [112], thinning of the

LV walls [103], onset of atrial fibrillation (AF) [113], spontaneous reduction or loss of LVOT obstruction [103–114], LV apical aneurysms [115] and variable patterns of intramyocardial fibrosis [116] that is inversely related to LV-EF.

**Overt dysfunction HCM Phenotype:** (5% of patients) is characterized by severe functional deterioration of the LV (LV-EF < 50%) secondary by extreme degrees of fibrosis and remodeling and generally associated with hemodynamic decompensation and adverse outcome [103, 105, 110, 117–119] with accelerated clinical deterioration of clinical condition. The morpho-functional manifestation of this stage can be summarized in two distinct and opposite phenotypical patterns: the hypokinetic-dilated form (LV dilation with spherical remodeling) [95, 110, 118, 119], that often may be hard to distinguish from a primary dilated cardiomyopathy, and the hypokinetic restrictive form (LV with small cavity and extreme diastolic dysfunction), mimicking a primary restrictive cardiomyopathy [94, 118–122]. In both forms, overt dysfunction represents the extreme consequence of adverse remodeling and the outcome in this stage is severe, not only due to high rates of HF-related complications and mortality but also because of a considerable incidence of SCD [95, 118–123].

#### **6. Management**

No evidence-based treatments are available for non-hypertrophic HCM patients (pre-hypertrophic stage) and avoiding competitive activity may be considered in these individuals for the risk of development of HCM or SCD although this issue remains highly controversial [95, 124]. In classic HCM, adverse remodeling and overt dysfunction phenotype, pharmacological or interventional strategies have the target to improve functional capacity, reduce symptoms, prevent disease progression. Therapeutic approach mainly differs on the basis of the presence or absence of LVOT obstruction (HOCM). Patients with HCM who are asymptomatic and have no evidence of arrhythmias or LVOT obstruction at rest or on effort generally do not require medical treatment [125]. In symptomatic HOCM patients, the aim is to improve symptoms by using drugs, surgery, alcohol ablation or pacing. In symptomatic patients without LVOT obstruction, the target of therapy is to reduce arrhythmic risk, LV filling pressures as well as improve symptoms such as dyspnea and angina. Patients with progressive LV systolic or diastolic dysfunction refractory to medical therapy may be candidates for cardiac transplantation.

#### **6.1 HOCM**

LVOT obstruction is defined as a peak instantaneous Doppler gradient of ≥30 mm Hg and the threshold for invasive treatment is usually considered to be ≥50 mm Hg. In general, all HCOM patients should avoid dehydration and excess alcohol consumption, and weight loss should be encouraged. Arterial and venous dilators, such as nitrates and phosphodiesterase type 5 inhibitors, can exacerbate LVOT obstruction and should be avoided [126]. HOCM symptomatic patients can be treated initially with non-vasodilating ß-blockers titrated to maximum tolerated dose. If ß-blockers alone are ineffective, disopyramide can be added, titrated up to a maximum tolerated dose [127, 128] because can abolish basal LV outflow pressure gradients and improve exercise tolerance and functional capacity without pro-arrhythmic effects [129–131]. Verapamil or ditiazem can be used when ß-blockers are contraindicated or ineffective [132–135]. Patients with HOCM (gradient ≥50 mm Hg,) and drug-refractory symptoms benefit from septal reduction therapy (SRT). Both septal myectomy and alcohol septal ablation (ASA) are

*Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

reasonable options when performed at experienced centres as part of a multidisciplinary team. Septal myectomy may be preferred when additional papillary muscle or mitral valve intervention can be performed, while ASA is favored for patients with elevated surgical risk [125]. Surgical myectomy has demonstrated excellent long-term efficacy and safety at selected high-volume centres with near-complete resolution of resting and inducible LVOT gradients. ASA showed similar perioperative mortality (about 1%) when compared to myectomy [136], although associated with a 10–15% rate of complete heart block, repeat procedures and increased risk of scar-related ventricular arrhythmias [137, 138]. Moreover, ASA is dependent on coronary anatomy since 15% of patients had unsuitable septal perforators [139]. In experienced centres, selective injection of alcohol into a septal perforator artery (or sometimes other branches of the left anterior descending coronary artery) to create a localized septal scar has outcomes similar to surgery in terms of gradient reduction, symptom improvement and exercise capacity [140–144]. Even in absence of randomized trials comparing surgery and ASA, several meta-analyses have shown that both procedures improve functional status with a similar procedural mortality [145–148].

#### **6.2 Symptomatic patients without LVOT**

In patients with normal LV-EF and no evidence of resting or provocable LVOT obstruction, aim of therapy is to reduce LV diastolic pressures and improve LV filling by slowing the heart rate with b-blockers, verapamil or diltiazem and cautious use of loop diuretics. Restoration of sinus rhythm or ventricular rate control is essential in patients who have permanent or frequent paroxysms of AF and digoxin is not recommended in patients with preserved EF because of the potentially adverse effects of positive inotropic stimulation [149]. ß-Blockers or calcium antagonists should be considered in patients with exertional or prolonged episodes of angina-like pain. Both classes improve diastolic function, reduce myocardial oxygen, thereby improving stress-induced sub-endocardial perfusion defects [150–154]. Patients with reduced LV-EF and HF symptoms should be treated with diuretics, ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) according to ESC guidelines for the management of chronic heart failure [155]. Moreover, CRT may be considered in individual patients with refractory symptoms, LV-EF < 35% and LBBB (QRS duration 120 ms) in accordance with current ESC Guidelines [156]. On the other hand, since LV-EF < 50%, rather than <35% as in primary or secondary dilated cardiomyopathies, is a strong discriminator of end-stage disease (associated with deteriorating HF and SCD) there is clear need for HCM disease-specific CRT and CRT-D criteria [57].

Orthotopic cardiac transplantation should be considered in patients with moderate-to-severe drug refractory symptoms (NYHA functional Class III–IV) and no LVOTO who meet standard eligibility criteria [157].

#### **6.3 Management atrial fibrillation and anticoagulation therapy**

Atrial fibrillation (AF) is the most frequent arrhythmia in HCM, affecting more than 20% of patients, and represents a marker of unfavorable prognosis, particularly when associated with LVOT obstruction and in patients younger than 50 years of age; moreover, the onset of AF worsens symptoms related to HF [158–160]. In haemodynamically stable patients, oral b-blockers or non-dihydropyridine calcium channel antagonists are recommended to slow the ventricular response to AF [161, 162]. Given the high incidence of stroke in patients with

HCM and paroxysmal, persistent or permanent AF, the current European Society of Cardiology (ESC) Guidelines of Atrial Fibrillation invite to do not use the CHA2DS2-VASc score to calculate stroke risk recommend that all patients with AF should receive treatment with OAC [163]. Similarly, the American Heart Association and American College of Cardiology (AHA/ACC) Guidelines recommended use direct-acting oral anticoagulants (NOAC) as first-line option and vitamin K antagonists as second-line option [57].

#### **6.4 Prevention of sudden cardiac death**

Adult patients with HCM report an annual incidence for cardiovascular death of 1–2%, with SCD, HF and thromboembolism being the main causes of death; the most commonly recorded fatal arrhythmic event is spontaneous ventricular fibrillation (VF), but asystole, AV block and pulseless electrical activity are described [2]. For this reason, SCD risk estimation is an integral part of clinical management of HCM [164]. Younger HCM patients are at higher risk for SCD than older patients [30, 165–171] since the 5-year cumulative proportion of SCD events is 8–10% from diagnosis in childhood HCM [172, 173]. In secondary prevention (patients which experiment cardiac arrest due to VT or VF or spontaneous sustained VT causing syncope or haemodynamic compromise), implantable cardioverter-defibrillator (ICD) implantation is indicated in all HCM patients. On the other hand, in primary prevention the best strategy to evaluated SCD risk seems to be a multiparametric approach. Recently, AHA/ACC guidelines suggest the evaluation of several risk factor for SCD based on personal and family history [165, 174–176], noninvasive testing including echocardiography [174, 177–179], ambulatory electrocardiographic 24 hours monitoring [180, 181] and CMR imaging [180–186] in order to identity those patients most likely to benefit ICD implantation [33, 168–170, 174, 187]. On the other hand, ESC guidelines [2] have proposed a risk score, named HCM Risk-SCD, that includes both clinical and instrumental data, thereby predicting annual risk of SCD and suggesting indication for ICD implantation (**Table 2**)**.** Subcutaneous ICD (S-ICD) may be considered in HCM patients who have no indication for pacing especially in patients that have a long life expectancy. However, particular attention should be paid to ensuring optimal R-wave sensing to avoid inappropriate shocks [2].

#### **6.5 New therapy prospective**

Novel therapeutic options are being evaluated and validated with diversified targets in the context of the physiopathology of hypertrophic cardiomyopathy.

**Myocardial Contractility and energetics**: Hypercontractility appears to play a central role in the pathogenesis of HCM since the vast majority of known mutations affect sarcomeric proteins, and ∼70% of identifiable mutations involving cardiac beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC) that contain the ATPase involved in actin–myosin cross bridging and muscle fiber shortening, thereby serving as the molecular motor for myocardial contraction [188–191]. It has been hypothesized that HCM mutations increase net power generation by the sarcomere resulting in LV hypercontractility and stiffening that is clinically observed. Mavacamten, a selective allosteric inhibitor of myosin ATPase capable of reducing the formation of bridges between actin and myosin at the sarcomere level and therefore of reducing contractility and improving the energy profile of the myocardium, helps ventricular hyper-contractility which has a pathophysiological role determinant in the genesis of the dynamic obstruction to the left ventricular outflow. It has been shown to improve exercise capacity, symptoms,


#### *Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

