FormalPara What You Will Learn in This Chapter

This chapter will begin by defining the term ‘cardiomyopathy’. From there, a comprehensive overview of the five main cardiomyopathies will be provided, both discussing the clinical signs and symptoms it manifests as, and also the science that underlies these changes. Where relevant, specific genetic mutations will be explored. This chapter ties together themes from earlier in the book, including the arrhythmogenicity of macro-reentrant circuits, the concept of contractility and the cardiomyocyte microstructure. Finally, new research surrounding Takotsubo cardiomyopathy will be explored.

FormalPara Learning Objectives

  • Discuss the causes of hypertrophic cardiomyopathy and the phenotype this produces.

  • Understand the distinct phenotypes of the five primary cardiomyopathies.

  • Appreciate the role of desmosome protein mutations in the development of arrhythmogenic right ventricular cardiomyopathy (ARVC).

12.1 Cardiomyopathy: The Fundamentals

‘Cardiomyopathy’ refers to a collection of ‘myocardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular and congenital heart disease sufficient to cause the observed myocardial abnormality’ [1]. First coined in 1952, this term came to refer three separate variants over the following decade, namely, hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies [2]. Subsequent imaging advances in the following resulted in the inclusion of further entities including arrhythmogenic right ventricular (ARVC) and so-called ‘unclassified’ cardiomyopathies such as Takotsubo, also referred to as ‘stress cardiomyopathy’ and ‘acute broken heart syndrome’. Importantly, with a prerequisite of this definition being both structural and functional abnormality, it therefore excludes channelopathies such as long QT and Brugada syndromes.

Of the five major categories of so-called ‘primary cardiomyopathy’ discussed, each can be classified into one of three major groups shown in ◘ Fig. 12.1, namely, genetic, acquired and mixed.

Fig. 12.1
figure 1

Classification of the five main variants of primary cardiomyopathy

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Catalysing the development of such categories has been an intensive effort to characterise genetic factors underlying the familial link of both the genetic and mixed cardiomyopathy phenotypes.

12.2 Hypertrophic Cardiomyopathy (HCM)

Hypertrophic cardiomyopathy (HCM), first described by Donald Teare in 1958, is characterised by cardiac hypertrophy independent of loading conditions, a non-dilated left ventricle (LV) and a normal or increased ejection fraction (EF) [3, 4]. It is mostly an autosomal disorder with variable penetrance [5]. HCM affects the sarcomere proteins and its associated protein, very rarely caused by autosomal recessive and X-linked modes of inheritance (e.g. Noonan syndrome [6], and Anderson–Fabry disease [7]. The commonest (30–50%) mutation is a missense (substitution) affecting gene Myh7, resulting in pathological alteration of ATPase activity and force generation of β-myosin heavy chains [8].

The second most common (20–40%) mutation affects gene Mybpc3 and is a frameshift mutation caused by insertion/deletion that has phenotypic consequences on myosin-binding protein C [9]. A smaller proportion of patients (5–20%) exhibit mutations to Tnnt2, a gene encoding an essential component of the cardiac troponin T complex required for actomyosin interactions in response to Ca2+ [10]. Other less frequently affected genes are Tpm1 (α-tropomyosin) and Tnni3 (cardiac troponin I), both of which have an incidence of <5%.

As previously discussed, the classical HCM phenotype is asymmetrical hypertrophy of the LV, typically affecting the basal interventricular septum with LV outflow tract (LVOT) obstruction. Of course, other phenotypic variants of HCM also exist, namely, mid-cavity, concentric, apical and biventricular hypertrophy, in addition to concentric hypertrophic with cavity obliteration, and also progressive LV wall thinning [11,12,13,14].

Symptomatically, typical HCM manifestations include fatigue, dyspnea, presyncope or syncope, chest pain and palpitations, although patients may rarely be asymptomatic [7]. The presence of LVOT obstruction may be asymptomatic until the commencement of exercise. The majority of HCM patients also exhibit non-specific ECG abnormalities of hypertrophy, with a variable proportion having repolarisation abnormalities, abnormal Q-waves and inverted T-wave [8].

The echocardiographic hallmarks of HCM are the appearance of hypertrophy as described above, with potential haemodynamic features of LVOT obstruction and systolic anterior motion of the mitral valve [7]. Valsalva, exercise or pharmacological stressors such as dobutamine or nitrate-based agents could accentuate or unmask LVOT obstruction [15]. Histopathological features of HCM may include myocyte hypertrophy, an irregular ‘chaotic’ distribution of cells and unorthodox-shaped nuclei, and the presence of interstitial and replacement fibrosis. The intramural coronary arteries often appear with thickened vessel walls and a decreased lumen size [16]. A combination of these factors precipitates potential complications of heart failure (HF), sudden cardiac death (SCD) and stroke from an increased risk of atrial fibrillation [7].

12.3 Dilated Cardiomyopathy (DCM)

Dilated cardiomyopathy (DCM) is defined by the dual presence of LV dilatation and contractile dysfunction. It is a mixed cardiomyopathy, with acquired DCM constituting the majority of cases and deriving from a variety of aetiological factors. Up to 40% of cases are due to genetic factors, with over 40 causative genetic mutations identified [17]. These affect proteins of the sarcomere [18] (most frequently truncation mutations affecting titin [19], Ttn, but also myosin, Myh6, Myh7, Mybpc3; and actin, Actc1 and Actc2), cytoskeleton [20] (desmin and cypher/ZASP), nuclear envelope [21] (limb-girdle muscular dystrophy, Emery–Dreifuss muscular dystrophy and autosomal dominant partial lipodystrophy), sarcolemma, ion channels and intercellular junctions. The latter two do not strictly belong to ‘primary muscle disorders’ to fit the definition of DCM.

In adult DCM, the usual mode of transmission is mostly autosomal dominant, commonly with partial and age-related penetrance and variable expression [22]. In paediatric and adolescent forms, autosomal recessive is the most common transmission pattern [23]. Phenotypically, DCM manifests as LV dilatation with impaired function (LVEF <40%) in the absence of hypertension, valvular heart disease and coronary heart disease [24]. The echocardiographic features of DCM include spherical dilatation of the LV, mitral regurgitation from annular dilatation and the potential appearance of pulmonary hypertension [24]. The global systolic cardiac function is reduced, and the diastolic function may show a restrictive filling pattern.

Patients with DCM may be asymptomatic for a number of years, with SCD an uncommon but notable first presentation of the disease. Typically, symptoms of HF occur over time, namely, a reduced exercise tolerance, dyspnoea and palpitations [25]. In contrast, the non-genetic (acquired) causes of DCM are diverse, some of which shown below in ◘ Table 12.1 [26,27,28,29].

Table 12.1 A summary of some notable non-genetic causes of DCM
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12.4 Restrictive Cardiomyopathy (RCM)

Restrictive cardiomyopathy (RCM) is the least common of the three subtypes in the original 1952 definition and appears phenotypically as a non-dilated left or right ventricle with normal wall thickness [30]. Diastolic dysfunction may reveal as restrictive filling (due to decreased myocardial compliance) with elevated filling pressures and dilated atria. Systolic function is often preserved, albeit not completely normal [30]. Classical symptoms of RCM include dyspnoea, peripheral oedema, ascites, palpitations, fatigue, weakness and exercise intolerance. Diagnosis is usually made via exclusions. As a mixed cardiomyopathy, its cause in any given patient can be classified into familial (genetic) or non-familial (acquired), with the majority of cases being the latter [30]. Some of these are shown in ◘ Table 12.2 [30,31,32]. Mutations to genes encoding several sarcomeric proteins have been associated with RCM when inherited in an autosomal dominant manner, namely, β-myosin heavy chain (Myh7), actin (Actc), troponin I (Tnni3) and troponin T (Tnnt2) [33].

Table 12.2 A summary of some notable causes of RCM
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12.5 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterised by the progressive replacement of myocardium by fibrofatty tissue in the RV [34]. Although non-ischaemic, the loss of myocardium results in regions of hypokinetic tissue, compromising the ventricle’s contractile capability. Typically, this deposition of fibrofatty tissue is initially localised to three areas: the inflow tract, outflow tract and RV apex in an arrangement referred to as the ‘triangle of dysplasia’ [35]. Whilst predominating in the RV, advanced cases of ARVC frequently involve the left ventricle as well, in addition to some subvariants of ARVC concentrated in the LV [36]. ARVC manifests as symptoms including syncope and shortness of breath (dyspnoea), both of which derive from compromised RV contractility and thus output, in addition to palpitations.

Importantly, it is not uncommon for the first presentation of ARVC to be sudden cardiac death (SCD), particularly in young adults and competitive athletes [37]. In one study conducted over a 10-year period in Veneto, Italy, ARVC constituted the most frequently encountered cause of sudden cardiac death in young adults, accounting for 27% of 22 cases [37].

Potentially underlying the association between the symptomatic expression of ARVC (including SCD) and exercise is the increased myocardial workload and subsequent adrenergic signalling. This is superimposing on a tissue interspersed with fibrofatty tissue that will slow conduction, providing a suitable substrate for the generation of macro-reentrant circuits and ventricular arrhythmias [38].

ARVC is considered a genetic cardiomyopathy and is usually inherited in an autosomal dominant manner, with incomplete penetrance and a variable expression pattern. That said, some rare recessive cases have been noted [39]. Across several studies, causative mutations are typically identified in 30–50% of affected individuals, with a high proportion being in genes encoding desmosomal proteins [38]. It was only following this discovery that AVRC, originally considered a congenital defect of the right ventricle, was re-classified as a cardiomyopathy [38]. Desmosomes are a subset of junctional complex that confers stronger intercellular adhesion in order to maintain the global structural integrity of a tissue [40]. They are particularly abundant in tissues exposed to significant mechanical stress, such as the mucosa of the gastrointestinal tract, the epidermis and the myocardium, to name a few [40].

A desmosome comprises five structural elements, namely, plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin-2. The encoding gene of each of the desmosome proteins is shown in ◘ Table 12.3.

Table 12.3 Table of the five constituent desmosome proteins and their encoding genes
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In a seminal 2000 paper by McKoy et al., mutations in the gene encoding plakoglobin, Jup, were the first identified as contributing towards the development of ARVC [41]. This finding renewed interest on intercellular adhesion proteins, with subsequent causative mutations later identified in each of the genes encoding the other four proteins. The most frequently mutated of these is plakophilin-2, encoded by Pkp2, with one study of 120 unrelated ARVC individuals identifying heterozygous Pkp2 mutations in 26.7% of cases [42].

The importance of desmosomes in the pathophysiology of ARVC is further supported by Basso et al. who used transmission electron microscope (TEM) to study the ultrastructure of intercalated discs obtained from ARVC patients. These were then compared against both control and DCM samples. The ARVC intercalated discs exhibited marked structural remodelling, including a reduction in the number of desmosomes and substantial elongation of those remaining. With desmosomes being the vital mechanical support structure of intercalated discs, a depletion in their representation represents a marked deterioration in the architectural stability of the heart as a functional syncytium. Specifically, with this reduction localised to the intercalated discs of the RV, a sudden increase in mechanical stress, such as that encountered during exercise, would represent a weakening of intercellular junctions in the ventricle.

12.6 Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TCM) was first discovered in 1990 by Sato et al. and derives its name from the Japanese word ‘takotsubo’, meaning ‘octopus pot’ [43]. This is due to the apical ballooning of the LV and resemblance this has to the aforementioned pot. Broadly, TCM has come to be characterised by transient and reversible systolic dysfunction concentrated in the middle and apical segments of the LV, with subsequent hypercontractility in the base of the heart [44].

Due to its association with physical and/or emotional stress, both of which frequently represent triggers of this cardiomyopathy, Takotsubo has also come to be known as ‘stress cardiomyopathy’ or ‘acute broken heart syndrome’ [43, 44]. Indeed, this is evidenced by Paur et al., who used an in vivo rat model to demonstrate the induction of mid-LV-to-apical hypocontractility (TCM) using high-dose IV adrenaline [44].

Likely underlying this distinctive phenotype is the heterogeneous distribution of β-adrenergic receptors (βAR) throughout the mammalian myocardium, with the apex characterised by the densest dispersion of receptors relative to the sparse proportion in the base [45, 46]. They form a broad βAR-response gradient that has been evidenced in several animal models [44, 47, 48].

Constituting ~90% of the total cardiac adrenergic receptors, βAR mediate many of the sympathetic nervous system (SNS) effects on the heart [49]. Briefly, catecholamines (especially adrenaline) bind to and activate βAR, triggering the exchange of GDP for GTP on the associated Gs alpha subunit. This facilitates dissociation of the G-protein, which is now able to activate adenylyl cyclase (AC), a 12-transmembrane domain enzyme that catalyses the conversion of ATP to cyclic 3′,5′-adenosine monophosphate (cAMP) and pyrophosphate using its C1a and C2a domains. Protein kinase A (PKA) is a holoenzyme composed of two regulatory and two catalytic subunits. cAMP binds to the two PKA regulatory subunits, causing dissociation from the catalytic subunits, which are now able to phosphorylate proteins, exerting many of the adrenergic effects, including positive inotropy (discussed further in ► Chap. 10).

However, β2AR is also able to exert signalling via an alternative Gi alpha subunit (and non-G-protein pathways altogether), with subsequent negative inotropic effects on the myocardium [44]. At high levels, adrenaline can ‘switch’ β2AR signalling to this pathway via the Gi alpha subunit in a process termed ‘biased agonism’. Consequently, at high adrenaline concentrations, the differential apical–basal expression of β2AR produces intraventricular variability in inotropy and the Takotsubo phenotype [44]. For this reason, TCM is classified as an acquired cardiomyopathy.

Take-Home Message

  • ‘Cardiomyopathy’ refers to myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular or congenital heart disease sufficient to cause the observed myocardial abnormality.

  • Primary cardiomyopathies can be classified into genetic (HCM, ARVC), acquired (TCM) and mixed (DCM, RCM) categories.

  • Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by the progressive replacement of myocardium by hypokinetic fibrofatty tissue, resulting in a loss of contractility in affected regions.