Inherited Heart Diseases

Chapter 21
Inherited Heart Diseases


The inherited heart diseases with risk of sudden death discussed in this chapter are listed in Table 21.1 (Bayés de Luna and Baranchuk 2017). In describing each of these processes, we will emphasize the importance of the ECG in reaching a diagnosis and in determining the clinical implications. Molecular, genetics, and many aspects related to sudden death are not considered in depth in this book (Ackerman et al. 2011). In this chapter, we include the heart diseases that are deemed to be due to inherited changes. Other heart diseases that are occasionally inherited, such as dilated cardiomyopathy (DC) or Wolff–Parkinson–White (WPW) syndrome, are discussed in other chapters. For more information, consult the general references (page XII).


Hypertrophic cardiomyopathy (Figures 21.121.4)

Concept and diagnosis

Hypertrophic cardiomyopathy (HCM) is usually a familial disease of genetic origin, characterized by alterations in proteins of the myocardial cells leading to myocardial fiber disarray, hypertrophy of the heart, and an increased incidence of sudden death. More than 500 mutations and 9 genes have been described. The more frequent mutations include troponin T (TNNTZ) and beta myosin heavy chain (MYH7).

The diagnosis is suggested by family history and ECG and is confirmed by echocardiography and other imaging techniques (Figure 21.3) (Maron et al. 2006).

The hypertrophy may cause a dynamic obstruction of the left ventricle outflow tract, and on some occasions it leads to DC and heart failure (HF). When the apex is preferentially involved in the cardiomyopathy, the ECG pattern shows typical features (Figure 21.2).

ECG findings (Figures 21.121.4 and Table 21.2)

Pathologic ECGs are observed in approximately 95% of cases, although there is no characteristic ECG alteration indicative of a specific mutation.

In contrast to what is observed in the inherited long QT syndrome, in HCM, it is not possible to predict the different mutations based on the ECG changes, and vice versa, except for some types of predominantly apical HCM (Arad et al. 2005).

However, there are some electrocardiographic patterns clearly indicative of HCM, in particular, a large negative and sharp T wave that is typical of apical HCM (Figure 21.2), as well as a narrow and deep Q wave associated with a positive T wave, suggestive of septal hypertrophy (Figure 21.1).

In patients with HCM, especially apical HCM, RS morphology may be observed in V1. This may be diagnosed mistakenly as right ventricular hypertrophy, but is in fact caused by septal hypertrophy. Thanks to the relationships between ECG and magnetic resonance imaging (MRI), it has become possible to locate the more hypertrophic areas with the ECG (Dumont et al. 2006).

Patients frequently show ECG signs of left ventricular enlargement, which are in some cases very characteristic (Figure 21.2). However, sometimes are impossible to distinguish from those found in other heart diseases. In these cases, imaging techniques play a major role in establishing the correct diagnosis (Figure 21.3).

The QRS voltage is usually increased with often clear criteria of LVH (Figure 21.2). However a low voltage associated with a higher incidence of DC during follow‐up may be seen (Ikeda et al. 1999) (Figure 21.4). Fragmentation of the QRS (fQRS) has been proved to be a predictor of poor evolution and arrhythmias in patients with HCM (Femenia et al. 2013).

Table 21.1 Inherited heart diseases with risk of sudden death

(Bayés de Luna and Baranchuk 2017).

  • Cardiomyopathies (alterations in myocardial protein)

  • Hypertrophic cardiomyopathy
  • Arrhythmogenic right ventricular dysplasia/cardiomyopathy
  • Spongiform cardiomyopathy (non‐compacted)
  • Dilated cardiomyopathy (sometimes)

  • Specific conduction system involvement:

  • Lenegre syndrome

  • No structural involvement: channelopathies (isolated alterations in ionic channels)

  • Long QT syndrome
  • Short QT syndrome
  • Brugada syndrome
  • Catecholaminergic ventricular tachycardia
  • Familial atrial fibrillation
  • Torsades de pointes ventricular tachycardia with short coupling interval (probably)
  • Idiopathic ventricular fibrillation (possible)
  • Others (possible)

At times the ECG alterations are observed before the echocardiogram shows any change. Therefore, an abnormal ECG may be the only evidence suggesting the presence of HCM in a patient’s relatives, or may oblige us to rule it out when it is a casual finding.

An increased interval T wave peak/T wave end may be a more significant risk marker of torsades de pointes ventricular tachycardia (VT) than the QT dispersion or even the corrected QT (QTc) (Yamaguchi et al. 2003).

Often patients with HCM present with arrhythmias in the ECG. The most frequent supraventricular arrhythmia is atrial fibrillation (≈10% of patients) (Britton et al. 2017). The resulting loss of the atrial contribution to the filling of a hypertrophied and stiff left ventricle results in clinical deterioration. The presence of premature ventricular complexes (PVCs) is also common; they are found in more than three‐quarters of patients wearing a Holter device. Runs of non‐sustained VT are found in one‐quarter of patients and its presence has prognostic implications. However, the presence of sustained VT is infrequent.

Very often, different types of blocks, especially intraventricular blocks (left bundle branch block, LBBB), are present in advanced cases.

Clinical implications

Most patients with HCM will likely develop left ventricular outflow obstruction (Maron 2010), although a clear dynamic pressure gradient in the left ventricular outflow tract is only seen in ≈30%. Some patients with HCM present with predominant apical involvement, which is more frequently observed in Japan (Suzuki et al. 1993).

Often, patients with HCM present with progressive dyspnea, especially after 40–50 years, due to diastolic dysfunction. Sometimes it is related to the appearance of atrial fibrillation. However, only about 10–15% of HCM patients will develop DC. The underlying physiopathologic mechanism that explains this evolution is not known with certainty. However, it has been shown that at 10‐year follow‐up, the incidence of HF is higher in patients with low‐voltage QRS complexes (SV1 + RV6 < 35 mm) (Figure 21.4). This is probably because the low voltage is a marker of increased fibrosis (Ikeda et al. 1999).

The few cases with normal ECG have a better prognosis (McLeod et al. 2009), even though some exceptions have been found in patients with troponin T alterations, family history, and evidence of fibrosis by MRI (see below).

The differential diagnosis with athlete’s heart constitutes an interesting challenge. There are clinical, ECG, and echocardiographic data on which we could base our differential diagnosis (Maron et al. 1981). If necessary, other techniques may be used to diminish the doubtful cases (gray zone in Figure 21.5) (Bayés de Luna et al. 2000; Zhang 2014).

Sudden death is the most important risk in this patient population. The yearly mortality rate is around 1%. Sudden death usually occurs during exercise due to a sustained VT leading to ventricular fibrillation (VF). This is the most common cause of sudden death in athletes. However, based on the experience of Maron (2010), more than 30 years may elapse before another cardiac arrest occurs. The most useful main risk factors of sudden death (McKenna and Behr 2002; Maron 2003, 2010) are:

  • familial history of sudden death;
  • personal antecedents of unexplained syncope;
  • multiple‐repetitive non‐sustained VT in Holter recordings;
  • abnormal blood pressure response during exercise testing;
  • massive right ventricle hypertrophy ≥20 mm, and especially ≥30 mm.

The presence of two, or even one for some authors (Maron 2010), of the abovementioned factors, especially when accompanied with genetic alterations (especially troponin T mutations), is associated with an increased risk of sudden death and requires implantable cardioverter defibrillator (ICD) implantation. Meanwhile, the absence of the abovementioned risk factors, especially family history of sudden death in patients older than 50–60 years, is indicative of a better prognosis.

In HCM, as happens in all other inherited heart diseases described in this chapter, the advantages of ICD implant always have to be balanced with the risk of complications (inappropriate shocks, infections, etc.) (Bayés de Luna and Baranchuk 2017).

Schematic illustration of the hypertrophic cardiomyopathy (HCM).

Figure 21.1 Hypertrophic cardiomyopathy (HCM). Deep “q” waves in anterolateral leads, which may be mistaken for those observed in ischemic heart disease. However, usually are narrow and fine.

Arrhythmogenic right ventricular dysplasia cardiomyopathy (Tables 21.3 and 21.4, Figures 21.6 and 21.7)

Concept and diagnosis

Arrhythmogenic right ventricular dysplasia cardiomyopathy (ARVC) is a familial disease of genetic origin, comprising both a recessive form and a dominant form. In 50% of cases, it is related to a mutation in the plakofilin gene. The disease is characterized by fatty infiltration and fibrosis localized especially in the right ventricle, leading to electrical instability and risk of sudden death. Frequently, left ventricle involvement exists as well.

The diagnosis must be made according to the criteria of the Task Force for Cardiomyopathy (McKenna et al. 1994). Recently, revised Task Force Criteria (Marcus et al. 2010) have been published (Table 21.3).

ECG findings (see Table 21.3)

The following are the ECG signs most frequently observed in ARVC (Jain et al. 2009; de Alencar Neto et al. 2018):

  • Prolonged QRS complex width in lead V1 greater than V6 (Fontaine et al. 2004). This is due to late right ventricular depolarization and explains that late potentials are in fact frequently positive (see Chapter 25) (Figure 21.6). This is reported in 80% of the cases.
  • Atypical pattern of right bundle branch block (RBBB). This is generally manifest as a wide R wave of relatively low voltage in lead V1 (Figure 21.6). It is also due to late right ventricular depolarization. This is found in 35% of cases.
    Schematic illustration of apical hypertrophic cardiomyopathy (HCM). The large negative T waves lead us to make a differential diagnosis with ischemic heart disease (IHD).

    Figure 21.2 Apical hypertrophic cardiomyopathy (HCM). The large negative T waves lead us to make a differential diagnosis with ischemic heart disease (IHD).

  • Negative T wave in precordial V1 to V3–V5 leads and sometimes in inferior leads and usually symmetric (Figures 21.6 and 21.7). Sometimes with mild ST segment elevation. This is observed in 50% of cases.
  • Occasionally (≈10% of cases), the late depolarization of the upper right ventricular wall is recorded as separate from the end of the QRS complex, showing subtle notches/undulations (ε wave), especially in the right precordial leads and frontal plane leads (Figure 21.8).
  • Abnormal P wave is seen in more than 10% of cases.
  • It is important to remember that the ECG may be normal in 20% of cases.
  • Frequently, ventricular arrhythmias are present. They originate in the right ventricle as isolated or repetitive PVCs (VT runs) with LBBB morphology, generally with left QRS axis deviation, although a right axis deviation is also possible (Figure 21.6 and Table 16.3). Sustained VT, sometimes at very high rate, is observed (Figure 21.7B), which may lead to aVF.

Clinical implications

ARVC may lead to a sustained and generally monomorphic VT with LBBB morphology, eventually leading to aVF and sudden death.

Schematic illustration of Top: ECG with left ventricular enlargement pattern not specific of any heart disease.

Figure 21.3 Top: ECG with left ventricular enlargement pattern not specific of any heart disease. Below: Cardiovascular magnetic resonance (CMR) (right) showing an asymmetric septal hypertrophy (asterisk), which confirms the diagnosis (HCM). Left: CMR with normal left ventricle image (for comparative purposes). It should be pointed out that echocardiography allows us to reach the same diagnosis.

Schematic illustration of a 50-year-old patient with familial hypertrophic cardiomyopathy.

Figure 21.4 A 50‐year‐old patient with familial hypertrophic cardiomyopathy. (A) Note the low‐voltage QRS and the diffuse repolarization alterations, as well as the presence of premature ventricular complexes (PVCs). Patients with hypertrophic cardiomyopathy usually exhibit a high voltage. It has been shown that the presence of relatively low voltages is associated with congestive heart failure (CHF) in the long‐term follow‐up. (B) In this case, after 15 years, the patient suffered from advanced CHF with atrial fibrillation, resulting in a very abnormal ECG: advanced right bundle branch block (RBBB) with pseudonecrosis q waves and a significant right QRS deviation due to right heart failure.

Table 21.2 ECG alterations in hypertrophic cardiomyopathy (Figures 21.121.4)

Abnormal ECG Abnormal in 95% of the cases. Sometimes with normal or slightly changed echocardiogram
Signs of left ventricular enlargement Frequent. Sometimes characteristic repolarization alterations are observed (Figure 21.2) (Large negative T wave, frequently very symmetrical and sharp). The ECG is frequently not distinguished from other processes which involve left ventricular enlargement (aortic stenosis, hypertension) (Figure 21.3)
QRS voltage is usually increased. If it is relatively low (SV1 + RV6 < 35 mm), the patient is likely to suffer from heart failure in the future (Figure 21.4)
Pathological Q wave Not very frequent
It is observed in leads where it is usually not seen
Narrow and sometimes very deep.
Generally the T wave is positive (Figure 21.1)
Repolarization alterations Very frequent (see above), sometimes with large negative but sharp T waves (Figure 21.2)

It is important to remember that small repolarization changes (Figure 21.7A) are enough to suspect the condition and that the ECG may be normal in about 20% of cases, and may initially mimic myocarditis (Pieroni et al. 2009).

When active arrhythmias of right ventricular origin are present (PVCs occurring frequently, above all during exercise, and runs of VT), and symptoms, such as syncope during exercise, are observed, a cardiac magnetic resonance (CMR) should be performed to confirm the ARVC. This technique is very useful in athletes to rule out or confirm this condition, and also HCM or an anomalous origin of the coronary arteries.

Frequently (>80% of cases), left ventricle involvement exists as well, often developing before the right ventricle is involved. Isolated left ventricular involvement is detected by the presence of a negative T wave in left lateral leads, PVCs of left ventricle origin, and imaging signs (CMR) of left ventricular dysfunction, without the evidence of right ventricular abnormalities (ECG, CMR) (Coats et al. 2009).

In the presence of sustained VT or frequent PVCs, ablation may be indicated, even though due to the presence of several foci frequent recurrences have been observed (Dalal et al. 2007) and for that its indication is controversial.

Schematic illustration of criteria used to distinguish hypertrophic cardiomyopathy (HCM) from an athlete’s heart when the left ventricular wall thickness is within the gray zone, consistent with both diagnoses.

Figure 21.5 Criteria used to distinguish hypertrophic cardiomyopathy (HCM) from an athlete’s heart when the left ventricular wall thickness is within the gray zone, consistent with both diagnoses

(Adapted from Bayés de Luna et al. 2000).

Implantable cardioverter defibrillator (ICD) therapy is considered the best treatment option, particularly in patients with a history of sustained VT/VF, patients with extensive left ventricular involvement, and those with a history of syncope (consult p. XI).

Spongiform or non‐compacted cardiomyopathy (Figure 21.9)

Concept and diagnosis

Spongiform or non‐compacted cardiomyopathy is a rare familial cardiomyopathy of uncertain etiology, for which a genetic origin has been proposed (Murphy et al. 2005). From an anatomo‐pathologic point of view, it is characterized by an increase in the trabecular mass of the left ventricle (non‐compacted), contrasting with a thin and compacted epicardial layer that may be visualized with imaging techniques (echocardiography and, above all, CMR) that confirm the diagnosis.

ECG findings (Figure 21.9)

Initial diagnosis is based on the following surface ECG features (Steffel et al. 2009):

  • intraventricular conduction disturbances (50%);
  • repolarization disorders, manifest especially as negative T waves in precordial leads (70%);
  • prolonged QT interval (50%);
  • left ventricular hypertrophy (30%);
  • normal ECG in 5% of cases.

Occasionally, the ECG is similar to that of some cases of ARVC (compare Figures 21.9 and. 21.7A). As the repolarization alteration disorder (negative T wave) is usually in the right precordial leads and not striking, it may be mistaken for normal ECG variations.

Table 21.3 ARVC: Summary of revised task force criteria (Marcus et al. 2010)

(Adapted from Marcus et al. 2010).

I Global or regional dysfunction and structural alterations

  • By 2D echo, MRI or RV angiography: Regional RV akinesia, dyskinesia, or aneurysm
  • By MRI: ↓RV ejection fraction (<40%‐major, 40–45% minor dysfunction)
II Repolarization abnormalities

  • Major: Inverted T wave (V1–V3) or beyond in individuals >14 years. No RBBB (Figure 21.7A)
  • Minor: Inverted T wave only in V1–V2 in individuals >14 years. No RBBB
  • Inverted T waves in V1–V4 individuals >14 years in presence of RBBB (Figure 21.6)
III Depolarization abnormalities

  • Epsilon wave in V1–V3 (Figure 21.8)
  • Localized prolongation of QRS in V1–V3 (>110 ms) compared with V6 (>20–30 ms)
  • Late potentials. In the absence, QRS ≥110 ms
IV Arrhythmias

  • Non‐sustained or sustained VT (LBBB morphology superior axis). Major criteria (Figure 21.7B)
  • Non‐sustained or sustained VT (LBBB morphology inferior axis). Minor criteria.
  • >500 PVC per 24 hours. (Holter) Minor criteria
V Family history

  • History of ARVC/D in a first‐degree relative
  • Premature sudden death (<35 years of age) due to suspected ARVC/D in a first‐degree relative
  • ARVC/D confirmed pathologically or by current Task Force Criteria in second‐degree relative

ARVC: arrhythmogenic right ventricular dysplasia cardiomyopathy; MRI: magnetic resonance imaging; PVC: premature ventricular complex; RBBB: right bundle branch block; RV: right ventricle; VT: ventricular tachycardia.

Clinical implications

The patient may remain asymptomatic for many years, but this cardiomyopathy eventually evolves into DC and HF. Sometimes embolism and/or ventricular arrhythmias appear in the follow‐up. Ventricular arrhythmias may trigger sustained VT/VF and sudden death.

Some cases need ablation, ICD, or even heart transplantation.

Specific conduction system involvement

Lenegre syndrome

Lenegre syndrome is a rare condition that consists of a progressive intraventricular conduction block without apparent heart disease. It appears in members of the same family at a relatively young age (Lenegre 1964).

Schematic illustration of typical ECG pattern of a patient with arrhythmogenic right ventricular cardiomyopathy.

Figure 21.6 Typical ECG pattern of a patient with arrhythmogenic right ventricular cardiomyopathy (ARVC). Note the atypical right bundle branch block (RBBB), premature ventricular complexes (PVCs) from the right ventricle, and negative T wave in V1–V4. We also see how QRS duration is clearly longer in V1–V2 than in V6. The patient showed very positive late potentials (right). Below: typical echocardiographic pattern showing the distortion of the right ventricular contraction (arrow).

Table 21.4 QTc prolongation in different age groups, based on the Bazett formula: values within the normal interval, borderline values, and altered values

Value 1–15 years old Adult (men) Adult (women)
Normal <440 ms <430 ms <450 ms
Borderline 440–460 ms 430–450 ms 450–470 ms
Altered (prolonged) >460 ms >450 ms >470 ms

From a genetic point of view, the Lenegre syndrome is caused by a Na channel dysfunction (decreased Na inflow into the cell). Histological studies show that a diffuse fibrotic degeneration of the whole intraventricular SCS exists, which may lead to an atrioventricular (AV) block without involvement of the sinus node and the fibrous skeleton of the heart. The presence of this evident pathologic involvement differentiates the Lenegre syndrome from channelopathies (see below).

Lenegre syndrome should be distinguished from Lev syndrome (Lev 1964), which is found in older patients and is caused by a non‐inherited senile degeneration of the SCS and the fibrous skeleton of the heart.

Usually, pacemaker implantation becomes necessary during the course of both Lenegre and Lev syndromes.

Ionic channel disorders in the absence of apparent structural heart disease: channelopathies

Exclusive alterations of the ionic channels are observed in long and short QT syndrome, Brugada syndrome, and catecholamine‐sensitive VT. They are also probably present in familial atrial fibrillation and other cases of sudden death due to other malignant ventricular arrhythmias, such as familial torsades de pointes VT and cases of VT that until now were considered idiopathic VF (Marbán 2002).

Schematic illustration of (A) Arrhythmogenic right ventricular cardiomyopathy (ARVC). (B) Very fast and not well-tolerated ventricular tachycardia (VT) in the same patient. It is initiated in the apex (left VT ÂQRS), a different site from where PVCs are generated.

Figure 21.7 (A) Arrhythmogenic right ventricular cardiomyopathy (ARVC). Note that apart from the premature ventricular complexes (PVCs), the only ECG abnormality is the symmetric and negative T wave in V1–V2, with flat T wave in V3–V4. It is important to assess these subtle changes when suspecting the diagnosis. (B) Very fast and not well‐tolerated ventricular tachycardia (VT) in the same patient. It is initiated in the apex (left VT ÂQRS), a different site from where PVCs are generated (see the different morphology in VF). Implantable cardioverter defibrillator implantation was performed.

Schematic illustration of an example of delayed depolarization wave following the QRS complex with a small separation and, generally, low voltage.

Figure 21.8 Example of delayed depolarization wave following the QRS complex with a small separation and, generally, low voltage (arrow). It is mainly observed in right precordial leads and in I, II, III, and aVR in some cases of arrhythmogenic right ventricular cardiomyopathy (ARVC). It is sometimes mistakenly taken for a very premature concealed atrial extrasystole. Note that in this case a high‐voltage P wave is observed and that a first‐degree atrioventricular (AV) block exists.

Some of the best‐known channelopathies show a typical phenotypic ECG pattern, which frequently allows for a correct diagnosis and even identification of the involved gene. There are some evidences showing that although initially isolated ionic alterations exist (true channelopathies), some ultrastructural changes may be present in the follow‐up (see below) (Frustaci et al. 2009; Bayés de Luna and Baranchuk 2017).

All channelopathies may increase the risk of developing different types of VT/VF, eventually leading to sudden death.

Long QT syndrome (Figures 21.1021.12)

Concept and diagnosis

We can only speak about long QT syndrome when a patient with apparent good health presents with a nonacquired long QT interval with syncopal attacks or recovered cardiac arrest due to torsades de pointes VT often leading to sudden death, or a family history of this syndrome.

The long QT syndrome is genetic channelopathy characterized by QTc prolongation in ECG and propensity to ventricular tachyarrhythmias (TdPVT, VF) leading to syncopal episodes and/or SCD. In about 10–15% of cases, QTc might remain within normal limit and in about 50% of cases, it will be categorized as borderline (between 440 and 470 ms). Table 21.5 lists ECG changes observed in the LQTS (Moss et al. 1985; Moss and Kan 2005).

Schematic illustration of ECG of an 18 year-old patient with repetitive sustained ventricular tachycardia (VT).

Figure 21.9 ECG of an 18 year‐old patient with repetitive sustained ventricular tachycardia (VT). In sinus rhythm, a clear QT prolongation is observed (>500 ms), as well as a negative T wave up to lead V3 with a flat T wave in V4–V6. This ECG may be mistaken for a normal ECG variant in a healthy subject. However, the long QT interval, the negative T wave up to V3, and the flat T wave in V4–V6 raise the suspicion of abnormal pattern. The echocardiogram allows for the diagnosis of spongiform cardiomyopathy.

Schematic illustration of the three examples of ECG patterns in long QT syndrome clearly associated with different chromosomal alterations: LQT1, LQT2, and LQT3.

Figure 21.10 Three examples of ECG patterns in long QT syndrome clearly associated with different chromosomal alterations: LQT1, LQT2, and LQT3.

Schematic illustration of ECG pattern from a child with a family history of congenital long QT syndrome. The long QT interval (QT = 520) is clearly seen, and the ST-T abnormal morphology in this case allows us to reach a diagnosis of congenital long QT syndrome.

Figure 21.11

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Oct 9, 2021 | Posted by in CARDIOLOGY | Comments Off on Inherited Heart Diseases
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