Journal of

Clinical Medicine

Review
Hypertrophic Cardiomyopathy and Primary Restrictive
Cardiomyopathy: Similarities, Differences and Phenocopies
Riccardo Vio 1 , Annalisa Angelini 1 , Cristina Basso 1 , Alberto Cipriani 1 , Alessandro Zorzi 1 ,
Paola Melacini 1 , Gaetano Thiene 1 , Alessandra Rampazzo 2,3 , Domenico Corrado 1, * and Chiara Calore 1

1 Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova,
35128 Padova, Italy; [Link].1@[Link] (R.V.); [Link]@[Link] (A.A.);
[Link]@[Link] (C.B.); [Link]@[Link] (A.C.); [Link]@[Link] (A.Z.);
[Link]@[Link] (P.M.); [Link]@[Link] (G.T.); [Link]@[Link] (C.C.)
2 Department of Biology, University of Padova, 35131 Padova, Italy; [Link]@[Link]
3 CRIBI Biotechnology Centre, University of Padova, 35131 Padova, Italy
* Correspondence: [Link]@[Link]

Abstract: Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have
a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These
“sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological
mechanism. Starting from the observation that patients with HCM and primary RCM may coexist
in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology
!"#!$%&'(! has been recently described and supports the hypothesis that familiar forms of primary RCM may
!"#$%&'
represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy.
Citation: Vio, R.; Angelini, A.; Basso,
To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease
C.; Cipriani, A.; Zorzi, A.; Melacini, P.;
and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to
Thiene, G.; Rampazzo, A.; Corrado,
left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among
D.; Calore, C. Hypertrophic
Cardiomyopathy and Primary
HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for
Restrictive Cardiomyopathy: cascade family screening and therapy.
Similarities, Differences and
Phenocopies. J. Clin. Med. 2021, 10, Keywords: hypertrophic cardiomyopathy; restrictive cardiomyopathy; cardiomyopathies; restrictive
1954. [Link] physiology; genetics; heart failure; amyloidosis; Fabry disease; glycogen storage diseases
10091954

Academic Editor: Martina Calore

1. Introduction
Received: 27 February 2021
Cardiomyopathies are a heterogeneous group of diseases of the myocardium asso-
Accepted: 28 April 2021
ciated with mechanical and/or electrical dysfunction, due to a variety of causes that are
Published: 1 May 2021
frequently genetic [1]. They can be either confined to the heart (“primary cardiomyopathy”)
or part of generalized systemic disorders (“secondary cardiomyopathy”), often leading to
Publisher’s Note: MDPI stays neutral
cardiovascular death or progressive heart failure-related disability [1]. The most common
with regard to jurisdictional claims in
cardiomyopathy is hypertrophic cardiomyopathy (HCM) caused by variants in sarcomeric
published maps and institutional affil-
iations.
(or sarcomere-related) genes, characterized by left ventricular hypertrophy in the absence
of another cardiac, systemic, or metabolic disease capable of producing the magnitude of
hypertrophy evident [2]. A key pathophysiological aspect of HCM is diastolic dysfunction,
which can be severe enough to determine a restrictive left ventricular filling pattern [3],
raising problems of differential diagnosis with primary restrictive cardiomyopathy (RCM).
Copyright: © 2021 by the authors.
Some familial forms of primary RCM have been described in patients carrying variants in
Licensee MDPI, Basel, Switzerland.
sarcomeric genes traditionally associated with HCM [4], and HCM and primary RCM may
This article is an open access article
coexist in the same family [5]. This scenario is further complicated by classifications that
distributed under the terms and
conditions of the Creative Commons
group cardiomyopathies based only on ventricular morphology and function irrespective
Attribution (CC BY) license (https://
of etiology [6,7]. According to these phenotypic classifications, some infiltrative and storage
[Link]/licenses/by/ diseases may be listed as either HCM or RCM depending on the degree of hypertrophy
4.0/). observed and left ventricular filling pattern (hypertrophic or restrictive phenocopies) [7].

J. Clin. Med. 2021, 10, 1954. [Link] [Link]

J. Clin. Med. 2021, 10, 1954 2 of 17

This review focuses on morphological, functional, and genetic features of HCM and pri-
mary RCM, offering guiding principles for differential diagnosis between them and among
cardiomyopathies that can present either with a hypertrophic or restrictive phenotype.

2. Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease caused
by a broad variety of genetic variants involving mostly proteins of the cardiac sarcomere.
Given its prevalence of 1:500 in the general population, it is considered the most common
genetic cardiovascular disease [1,2]. A left ventricular wall thickness of at least 15 mm
(or 13 mm in relatives) is considered sufficient for diagnosis, in the absence of other sys-
temic or cardiac diseases capable of producing the magnitude of hypertrophy evident (e.g.,
hypertension and aortic stenosis) [2]. At least 1400 variants in numerous genes encoding
proteins of the cardiac sarcomere responsible for (or associated with) HCM have been
identified [8]. The most commonly involved genes are MYH7, MYBPC3 (these two genes
include approximately 80% of all identified variants), TNNT2, and TNNI3. The majority of
patients reveal increased wall thickness by early adulthood [9,10], however different vari-
ants can demonstrate substantial variability in age-related penetrance, resulting in delayed
expression after the third decade of life, or even beyond mid-life [11,12]. The phenotype in
the first-degree family members also shows a wide range of expression, underscoring the
importance of other factors including modifier genes and epigenetics [13,14].
Twelve-lead ECG has traditionally been an integral part of non-invasive evaluation of
patients with HCM [15,16]. The vast majority of patients show an abnormal ECG tracing,
with a reported prevalence of ECG abnormalities of >90% [17]. Left ventricular hypertro-
phy, ST-segment depression, T wave inversion, pathologic Q waves, left atrial enlargement,
and left axis deviation are among the striking ECG abnormalities [15]. Atrial fibrillation
is reported in 20% of cases, being associated with heart failure progression [18–20]. On
the contrary, a normal ECG may predict a less severe HCM phenotype and a better car-
diovascular outcome [15,21,22]. Echocardiography is the primary non-invasive imaging
technique for diagnosis and risk stratification of HCM [22]. One third of patients have
resting left ventricular outflow tract obstruction (>30 mmHg) and another third have latent
obstruction that can be unmasked during provocative maneuvers [23]. Mitral regurgitation
is a common finding as the result of systolic anterior motion of the mitral valve, and
together with diastolic dysfunction leads to the enlargement of the left atrium. Diastolic
dysfunction can be severe enough to produce a left ventricular restrictive filling pattern,
defined as the ratio of mitral peak velocity of early filling (E) to mitral peak velocity of late
filling (A) 2 or an E-wave deceleration time  150 ms. Biagini et al., reported a restrictive
left ventricular filling pattern in 5.9% of 239 consecutive HCM patients at baseline, with
another 9.1% of them who developed this pattern during follow-up [3]. Another sign of
severe diastolic impairment is the triphasic left ventricular filling pattern (showing an
additional mid-diastolic filling wave) that can be found in up to one quarter of patients,
particularly those with thin-filament gene variants [24]. Systolic function is usually normal
or increased, until the development of the end-stage phase. Cardiovascular magnetic
resonance (CMR) allows precisely measuring wall thickness (especially at the apex and
lateral free wall), cardiac chamber volumes, and left ventricular mass. Myocardial fibrosis
is revealed by the injection of gadolinium-based contrast agents in 65% of patients [25,26].
Diffuse and extensive late gadolinium enhancement at CMR, either quantified or estimated
by visual inspection (comprising 15% of left ventricular mass) is now considered an es-
tablished risk factor for sudden death [2]. Endomyocardial biopsy is not part of the routine
diagnostic workup of HCM, but may instead be helpful when myocardial infiltration or
storage disease is suspected. Histopathological features of HCM include myocyte disarray,
increased interstitial fibrosis and abnormal intramural arterioles with thickened walls and
narrowed lumen [27–29]. In a large autopsy-based study, coronary artery bridges were a
frequent morphological component of phenotypically expressed HCM [30].
J. Clin. Med. 2021, 10, 1954 3 of 17

Patients’ clinical courses are heterogeneous, ranging from benign to sudden cardiac
death, being the leading cause of athletic field cardiac arrest in the USA, where it accounts
for more than a third of fatalities [31,32]. Different profiles of heart failure in HCM may
occur at any age due to diverse pathophysiological mechanisms, including left ventricular
outflow obstruction and diastolic or global systolic ventricular dysfunction [23,33,34].
According to Melacini et al., nearly half of patients with advanced heart failure occur in
the clinical setting of non-obstructive disease with preserved systolic function, presenting
a particularly malignant prognosis with earlier symptom onset [29]. This “restrictive
subgroup” of HCM patients show small ventricular cavities, markedly enlarged atria and
mild left ventricular hypertrophy with a restrictive left ventricular filling pattern (Figure 1).

Figure 1. Restrictive form of heart failure due to diastolic dysfunction in a 28-year-old patient with non-obstructive
hypertrophic cardiomyopathy preserved systolic function and troponin I variant. (A) Four-chamber view in end-diastole
showing dilatation of both atria (left atrium, LA = 53 mm), normal-sized ventricles, and mild ventricular septal (VS)
thickening (17 mm). (B) Pulsed Doppler waveform with evidence of restrictive filling: E/A>2; deceleration time, 150 ms.
(C) Long-axis left ventricular (LV) plane with mild VS hypertrophy (17 mm); atria missing due to transplantation. (D,E) LV
free wall (D) and septum (E) showing diffuse myocardial disarray, mild interstitial fibrosis, and intramural small vessel
disease. Trichrome stain ⇥ 40. LVFW: left ventricular free wall; RA: right atrium; RV: right ventricle. Reproduced with
permission from [29].
J. Clin. Med. 2021, 10, 1954 4 of 17

When hypertrophy is mild, differential diagnosis with RCM can be difficult and a
phenotypic overlap between these two entities may exist. Evaluating 1226 patients from 688
families with HCM, Kubo et al. advanced the “restrictive phenotype” (i.e., no or minimal
left ventricular hypertrophy of 15 mm and severe diastolic dysfunction) as part of the
clinical spectrum of HCM [35]. The authors concluded that the “restrictive phenotype” is an
uncommon presentation of HCM (19/1266, 1.5% of cases), associated with severe functional
limitation and poor prognosis, resembling idiopathic RCM. Sarcomeric gene variants were
identified in eight probands, including variants in MYH7 and TNNI3. However, not all
family members with the same variant developed the “restrictive phenotype” suggesting
that other genetic (e.g., modifier genes), epigenetic or environmental factors are involved.
Our research group recently reported a novel missense variant in the MYL2 gene associated
with HCM showing high incidence of restrictive physiology (Figure 2) [36]. Specifically,
38% of MYL2 carriers in our kindred had a restrictive filling pattern, much higher than
previously reported [3], and one patient showed the “restrictive phenotype” defined by
Kubo et al. [35]. Probably linked to the severe diastolic dysfunction, up to 62% of MYL2
carriers experienced atrial fibrillation and many patients had a poor clinical outcome.

Figure 2. Novel Missense variant in MYL2 gene and hypertrophic cardiomyopathy associated with a
high incidence of restrictive physiology. (A) Pedigree of the family. (B) Electrocardiogram of subject
J. Clin. Med. 2021, 10, 1954 5 of 17

III-25 showing first-degree AV block and left anterior hemiblock (prior to pacemaker implantation).
(C) Four-chamber echocardiographic view of subject III-25 showing biatrial enlargement and septal
hypertrophy (prior to pacemaker implantation). (D) Gross view of the left cardiac chambers of
subject III-25: note the severe dilatation of the left atrium with an almost preserved left ventricular
volume. The thickness of the LV free wall and ventricular septum are 13 and 14 mm, respectively, in
keeping with symmetric mild hypertrophy. (E) Histology of the LV free wall of subject III-25: note
the diffuse disarray of the cardiac myocytes with tiny interstitial fibrosis (trichrome stain). Modified
and reproduced with permission from [36].

3. Primary Restrictive Cardiomyopathy

Primary RCM is a rare myocardial disease characterized by normal or decreased
volume of both ventricles associated with biatrial enlargement, normal left ventricular
wall thickness, impaired ventricular filling with restrictive physiology, and normal or near-
normal systolic function [1]. Since the first report of a familial form caused by a cardiac
troponin I (TNNI3) variant [4], primary RCM was believed to be a sarcomeric disease
and was labeled together with HCM as a sarcomeric cardiomyopathy (“sarcomyopathies”)
according to a genomic/postgenomic classification [37–40]. Successively, apart from a small
subset of rare nonsarcomeric variants (myopalladin, filament-C, desmin, and alpha-beta
crystallin [41–44]), mounting evidence supported this view. Moreover, “desminopathies”
(i.e., familial RCM with variants in the desmin gene) should be classified as a separate
and secondary cardiomyopathy, given the almost invariable skeletal muscle involvement
producing a skeletal myopathy [43]. The most common sarcomeric gene variants associated
with primary RCM involve troponin T (TNNT2), alpha cardiac actin (ACTC), myosin-
binding protein C (MYBPC3), tropomyosin 1 (TPM1), and myosin light chain 2 (MYL2)
and 3 (MYL3) [45–48]. Moreover, TNNI3, MYH7, and MYL2 variants were reported as
responsible for some familial cases of HCM with “restrictive phenotype” (phenotypes
diagnostic of RCM) [4,36]. The coexistence of HCM and RCM phenotypes in the same
families with the same disease-causing variants led to the hypothesis that familiar forms
of RCM may represent a part of the phenotypic spectrum of HCM rather than a different
genetic cardiomyopathy [5,49].
The phenotypic expression of other cardiomyopathies (e.g., infiltrative and storage
disorders, endomyocardial fibrosis and sarcoidosis) may mimic primary RCM [1,50,51].
However, in primary RCM the morphologic and hemodynamic abnormalities occur in
the absence of specific histopathological changes [50,51] and possible findings include
interstitial fibrosis, myocyte hypertrophy, and myocardial disarray as in HCM [5,38,52].
The key aspect of primary RCM is the impairment of the ventricular filling dynamics
that ultimately lead to the increase of ventricular end-diastolic pressures and atrial dilation.
Such diastolic impairment is responsible for the development of progressive heart failure
symptoms (dyspnea, fatigue, and exercise intolerance). Cardiac catheterization shows
increased ventricular filling pressures with the typical dip-and-plateau or square-root sign;
left ventricular diastolic pressure is usually 5 mmHg higher compared to the right one
due to imbalanced involvement and compliance of the two chambers [51]. Equalization
of ventricular diastolic pressures is more typical of constrictive pericarditis but it may be
present and does not rule out the diagnosis of primary RCM [51,53]. Differential diagnosis
between these two conditions is usually straightforward: history of chronic pericarditis,
cardiac surgery, or chest irradiation favors the diagnosis of a constrictive pericarditis.
Non-invasive diagnostic testing (echocardiography, CMR, and cardiac computed tomog-
raphy (CT)) or invasive hemodynamic study are able to unveil characteristic features
of constrictive pericarditis including a thickened pericardium (>4 mm), interventricular
dependence, and dissociation between intracardiac and intrathoracic pressures during
respiration [53]. CMR is also helpful to differentiate primary RCM with secondary forms
of RCM due to infiltrative or storage diseases which show typical radiological findings (see
below) (Figure 3). Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is
indicated in case of clinical suspicion of sarcoidosis [54].
J. Clin. Med. 2021, 10, 1954 6 of 17

Figure 3. Representative cardiac magnetic resonance findings of patients with obstructive hyper-
trophic cardiomyopathy, hypertrophic cardiomyopathy with restrictive phenotype, amyloidosis,
and Fabry disease. (A) Obstructive HCM with intramural septal LGE. (B) HCM with restrictive
physiology (MYH7 variant) with massive septal fibrosis and severe atrial enlargement. (C) Light
chain immunoglobulin (AL) amyloidosis with transmural septal LGE. (D) Wild-type transthyretin
(ATTRwt) amyloidosis with LGE particularly in the right ventricle and atria. (E) Fabry disease with
hypertrophic phenotype and subendocardial LGE at the basal lateral segment of the left ventricle.
(F) Fabry disease with mild hypertrophy and intramural LGE at the mid-lateral segment of the left
ventricle and apex. HCM: hypertrophic cardiomyopathy; LGE: late gadolinium enhancement.

As happened for all the other principal cardiomyopathies, before the understanding
of molecular genetics of the disease primary RCM was referred to as “idiopathic” RCM [50].
The largest series is derived from the study of Ammash et al., who described 94 cases of
idiopathic RCM collected between 1979 and 1996, after excluding patients with known
ischemic, hypertensive, valvular, congenital, or pericardial heart disease and other condi-
tions such as amyloidosis, hemochromatosis, and eosinophilic syndrome [55]. According
to the study results, idiopathic RCM can occur at any age and mostly in women. The ECG
was almost invariably abnormal, with the majority of patients showing atrial fibrillation
J. Clin. Med. 2021, 10, 1954 7 of 17

(74%) and nonspecific ST-T wave abnormalities (80%); intraventricular conduction delay
was reported in 19% of patients and premature ventricular beats in 14%. Of note, none
of the patients had left ventricular hypertrophy (typical of HCM) or low QRS voltages
(typical of amyloidosis, see below). At the echocardiogram all patients showed biatrial
enlargement, nondilated ventricles with normal wall thickness; transmitral valve Doppler
showed either E-wave deceleration time of <150 ms or an E/A ratio > 2. None of the biopsy
specimens demonstrated amyloid or iron deposition, caseating granulomas, eosinophilic
or lymphocytic infiltrates, or any interstitial inflammatory changes.

4. Cardiomyopathies with either Hypertrophic or Restrictive Phenotype

Some infiltrative and storage diseases may present as phenocopies of either HCM
or primary RCM, according to the degree of hypertrophy observed and left ventricular
filling pattern (Figure 4). If maximal left ventricular wall thickness is at least 15 mm,
they must be differentiated from sarcomeric HCM. Otherwise, the restrictive physiology
inherent to the pathological process of myocardial infiltration or storage yields a phenotype
similar to that of primary RCM. Unmasking the underlying disease and going beyond
the ventricular morphology and function, is crucial in order to establish prognosis, guide
reproductive choices, and offer specific therapy to the patient. Age of onset is among the
factors to consider for differential diagnosis: for instance, glycogen storage diseases are
more common in infants, whereas ATTRwt amyloidosis involves predominantly men over
the age of 65 years [56,57].

Figure 4. Phenotypes of hypertrophic cardiomyopathy, primary restrictive cardiomyopathy, amyloidosis, Fabry disease,
and glycogen storage diseases. LVMWT: left ventricular maximal wall thickness.
J. Clin. Med. 2021, 10, 1954 8 of 17

Herein we describe the cardiomyopathies that can show either a hypertrophic or

a restrictive phenotype. Table 1 reports the full list of HCM and primary RCM pheno-
copies, and Table 2 summarizes the common diagnostic findings of HCM, primary RCM,
amyloidosis, Fabry disease, and glycogen storage diseases.

Table 1. Phenocopies of hypertrophic cardiomyopathy and primary restrictive cardiomyopathy.

Phenocopies
Hypertrophic Cardiomyopathy Primary Restrictive Cardiomyopathy
Infiltrative diseases: Infiltrative diseases:
-Amyloidosis -Amyloidosis
Storage diseases:
-Fabry disease
Storage diseases:
-Glycogen storage diseases
-Fabry disease
-Haemochromatosis
-Glycogen storage diseases
RASopathies *:
-Noonan syndrome Endomyocardial diseases:
-LEOPARD syndrome -Endomyocardial fibrosis
-Costello syndrome -Hypereosinophilic syndrome
-Cardiofaciocutaneous syndrome
Mitochondrial diseases (MELAS) Sarcoidosis
Carnitine disorders Scleroderma
Friederich’s ataxia Pseudoxanthoma elasticum
Beckwith–Wiedemann syndrome Carcinoid heart disease
Infant of diabetic mother Metastatic cancers
Drugs (tacrolimus, hydroxychloroquine,
Drugs (anthracyclines)
steroids)
Radiation
Cardiomyopathies highlighted in bold can show either a hypertrophic or restrictive phenotype. * Developmen-
tal disorders caused by germline variants in genes that encode components or regulators of the Ras/MAPK
pathway [58].

Table 2. Common diagnostic findings of hypertrophic cardiomyopathy, primary restrictive cardiomyopathy, amyloidosis,
Fabry disease, and glycogen storage diseases.

Glycogen Storage
HCM Primary RCM Amyloidosis Fabry Disease
Diseases
Increased QRS voltages,
Normal QRS voltages, Increased QRS
Increased QRS voltages, Low QRS voltages, Q waves short PR interval,
ST-T wave changes, voltages, short PR
ST-T wave changes, and QS complexes, AV pathologic Q waves, T
ECG atrial fibrillation, interval, T wave
pathologic Q waves, blocks and bundle branch wave inversion, sinus
intraventricular abnormalities, AV
LAE, LAD blocks bradycardia, AV blocks,
conduction delay blocks
bundle branch blocks
Mild concentric left
Mild to severe ventricular hypertrophy, Concentric left ventricular
Normal to extreme
asymmetrical, concentric right ventricular hypertrophy without
left ventricular
or apical hypertrophy. Nondilated ventricles hypertrophy, thickening of LVOT obstruction. Left
hypertrophy with
LVOT obstruction. Left with normal wall valves and atrial septum, atrial enlargement,
possible LVOT
Echo atrial enlargement. thickness, biatrial pericardial effusion, valvular thickening, right
obstruction, diastolic
Mitral regurgitation. enlargement, restrictive “granular” appearance of ventricular hypertrophy.
dysfunction, and
Diastolic dysfunction filling pattern myocardium, “apical Diastolic dysfunction
restrictive filling
(from mild to restrictive sparing” at global (from mild to restrictive
pattern
physiology) longitudinal strain, physiology)
restrictive filling pattern
Diffuse subendocardial LGE
(“zebra pattern”), difficulty Mid-mural LGE on basal
LGE in most LGE and high T1
in nulling the myocardial segment of
hypertrophied values in the
CMR - signal on phase sensitive non-hypertrophied
regionsHigh native T1 advanced stage of the
inversion recovery inferolateral wall. Low
values disease
sequences. High native T1 native T1 values
values
J. Clin. Med. 2021, 10, 1954 9 of 17

Table 2. Cont.

Glycogen Storage
HCM Primary RCM Amyloidosis Fabry Disease
Diseases
Apple-green birefringence
under polarized light Concentric lamellar bodies Vacuoles containing
Myocyte hypertrophy, Interstitial fibrosis,
microscopy using Congo red (degraded products of glycogen that stain
EMB myocardial disarray, myocyte hypertrophy,
staining. Randomly oriented globotriaosylceramide in positive with
interstitial fibrosis myocardial disarray
and non-branching fibrils at the sarcoplasm) periodic Acid Schiff
electron microscopy
ECG: electrocardiogram; Echo: echocardiogram; CMR: cardiac magnetic resonance; EMB: endomyocardial biopsy; LAE: left atrial
enlargement; LAD: left axis deviation; LVOT: left ventricular outflow tract; LGE: late gadolinium enhancement; AV: atrioventricular.

4.1. Amyloidosis
Amyloidosis is a systemic syndrome that represents the archetype of the infiltrative
form of RCM. Extracellular deposition of insoluble amyloid fibrils involves a variety of
organs including the heart, leading to cardiomyocyte separation, cellular toxicity, and apop-
tosis. Overall, these morphological changes increase myocardial stiffness causing diastolic
disfunction and heart failure. The three most common types of amyloidosis affecting the
heart (“cardiac amyloidosis”) are AL, ATTRwt, and mutant transthyretin (ATTRm) amy-
loidosis. AL amyloidosis is a rare hematological disorder, in which there is an increased
production of monoclonal kappa or lambda light chains that tend to misfold favoring tissue
deposition. Transthyretin is a protein with tetrameric configuration, produced mainly in
the liver; its monomers have amyloidogenic properties. ATTRm amyloidosis is a heritable
autosomal disorder caused by variants in the TTR gene that increase the likelihood of the
TTR tetramer to dissociate into monomers and form amyloid fibrils. In the absence of TTR
pathogenic variants, spontaneous dissociation of TTR tetramers may occur (usually later
in life), determining ATTRwt amyloidosis (senile amyloidosis). AL amyloidosis is rare
and has an estimated prevalence of 8 to 12 per million [59–61], although emerging data
suggest that ATTRwt amyloidosis is not uncommon: it may affect up to 13% of patients
hospitalized for heart failure with preserved ejection fraction [62]. Variants in the TTR
gene causing ATTRm amyloidosis are relatively rare but are endemic in some geographic
regions (e.g., Portugal and Sweden) [63].
Clinical presentation is useful, per se, in the differential diagnosis with sarcomeric
cardiomyopathies, as patients with amyloidosis show variable extracardiac organ involve-
ment. Peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia,
nephropathy, and hepatopathy are red flags for amyloidosis and should be sought in all
patients [64]. At the ECG, low voltages are reported in 20–60% of patients and mostly in
those with AL amyloidosis [65,66]. Pseudoinfarction patterns (Q waves or QS complexes)
are common (70% of cases), as they also are in HCM [15,67]. A significant percentage of
patients with amyloidosis develop progressive atrioventricular conduction disturbances
or bundle branch blocks [67]. Echocardiography reveals a concentric thickening of the
left ventricular free wall and septum, that is usually greater in patients with ATTRwt
amyloidosis [68]. Unlike HCM, right ventricular free wall, valves and atrial septum are
also thickened. According to a study by Quarta et al. who analyzed 172 patients with
AL, ATTRm or ATTRwt amyloidosis, a third of the overall population (n = 63) showed
a mean left ventricular wall thickness (almost identical to the interventricular septum
thickness given the concentric hypertrophy) of 15 mm (range 11.5–15 mm), and the other
two thirds >15 mm [68]. A restrictive filling pattern was found in 35% of patients. From
these data it is clear how the phenotype of patients with amyloidosis may mimic either
HCM or primary RCM. Some peculiar although nonspecific echocardiographic findings of
amyloidosis that may guide differential diagnosis are the following: right ventricular free
wall, valves and atrial septum thickening, pericardial effusion and “granular” appearance
of the myocardium [69]. Early signs of cardiac amyloid infiltration are the reduced basal
longitudinal strain compared to the normal or supranormal apical longitudinal strain (“api-
cal sparing”) and low septal and lateral early diastolic mitral annular velocities (E’-wave)
J. Clin. Med. 2021, 10, 1954 10 of 17

at tissue-Doppler echocardiography [64,70]. CMR can provide further clues to the diag-
nosis of amyloidosis by showing a characteristic diffuse subendocardial late gadolinium
enhancement (“zebra pattern”), and difficulty in nulling the myocardial signal on phase
sensitive inversion recovery sequences [71–73]. Bone scintigraphy imaging has recently
gained crucial relevance, since it has high specificity and a positive predictive value of
100% for transthyretin amyloidosis in case of moderate to high tracer uptake [64]. In the
absence of detectable monoclonal protein in serum or urine, bone scintigraphy allows
non-histological diagnosis of transthyretin amyloidosis [74]. However, tissue diagnosis
remains the gold standard. Congo red staining binds to the deposits of amyloid fibrils and
yields characteristic apple-green birefringence under polarized light microscopy. Electron
microscopy demonstrates randomly oriented and non-branching fibrils and subsequently
immunohistochemistry or laser microdissection/mass spectroscopy allows the subtyping
of amyloid fibril [75,76].
The treatment of amyloidosis goes beyond the purpose of the present review, but
novel specific therapies improving cardiac and neurological outcomes have been recently
approved and its recognition is therefore of paramount importance [77,78].

4.2. Storage Diseases

4.2.1. Fabry Disease
Fabry disease is a lysosomal storage disease with an X-linked recessive inheritance
caused by variants in the GLA gene, that determine an absent or deficient activity of lysoso-
mal alpha galactosidase A. As a result, globotriaosylceramide accumulate within virtually
all cell types’ lysosomes, leading to cellular death, inflammation, oxidative stress, and
fibrosis; cardiomyocyte hypertrophy results from increased concentrations of sphingolipid
and vascular smooth muscle cell proliferation [79]. The prevalence of Fabry disease is
estimated to be 1/3000–1/8000 newborns [80,81]. Indeed, near 1% of HCM population can
be newly diagnosed with Fabry disease when screened for this condition [82]. First signs
of the disease appear during childhood or early adulthood in men; women are diagnosed
later in life and show a better prognosis, considering the pattern of inheritance of the
disease (X-linked recessive transmission) [79]. In adults, clinical signs of Fabry disease
include a variable combination of kidney, neurological, and cardiac dysfunctions. Cardiac
symptoms occur in the majority of patients, and include dyspnea, heart failure, angina
caused by microvascular dysfunction, palpitations, and syncope [83]. Patients with Fabry
disease most often present with left ventricular hypertrophy, sometimes as a predominant
or isolated feature (“cardiac variant”) [81,84]. Left ventricular hypertrophy is the most
frequent cardiac sign, reported in over a half of men and one third of women [83]. Other
diagnostic red flags for Fabry disease are kidney disease, stroke, angiokeratoma corporis
diffusum, and cornea verticillate [79,85]. Arrhythmic manifestations include chronotropic
incompetence, sinus node dysfunction, advanced atrioventricular block, atrial fibrillation,
ventricular tachycardia, and ventricular fibrillation leading to sudden death [86].
The electrocardiogram often displays increased QRS voltages as the result of the
deposition within the cardiomyocytes rather than in the interstitium as it occurs in in-
filtrative disease (e.g., amyloidosis) characterized on the contrary by low QRS voltages.
Other ECG changes that can be seen in Fabry disease patients include a short PR inter-
val, sinus bradycardia, atrioventricular conduction disturbances, bundle branch blocks,
pathologic Q waves, negative T waves, and atrial fibrillation [81,83,87,88]. Supraventric-
ular and ventricular arrhythmias are common in Fabry disease and may occur even in
the prehypertrophic phase before any clinical or cardiac imaging abnormalities [81,89].
At the echocardiogram, left ventricular hypertrophy is frequently encountered (almost
invariably concentric), without left ventricular outflow obstruction or systolic dysfunc-
tion [90]. However, asymmetrical hypertrophy and subaortic obstruction have also been
reported, mimicking the phenotypical and clinical features of sarcomeric HCM [91]. Other
characteristics that may be documented are left atrial enlargement, valvular thickening
and right ventricular hypertrophy [90,91]. These latter findings are similar to those of
J. Clin. Med. 2021, 10, 1954 11 of 17

patients with amyloidosis, but further similarities between Fabry disease and amyloidosis
exist. In fact, even in Fabry disease the reduced tissue-Doppler velocities at the mitral
annulus can be the earliest signs of intrinsic myocardial relaxation impairment, preceding
left ventricular hypertrophy [92]. Diastolic dysfunction progressively worsens until the
development of a restrictive filling pattern [79]. Mid-mural late gadolinium enhancement
on basal segment of the inferolateral left ventricular free wall is a typical finding at the
CMR, often occurring on a non-hypertrophied wall [93]. Conversely, in HCM the site of
predilection for LGE accumulation is the part with the greater hypertrophy [94]. More-
over, T1 mapping helps in the refinement of differential diagnosis with either HCM or
amyloidosis. Sphingolipid storage in the myocardium yields low native T1 values which
are specific for Fabry disease, as opposed to the other two conditions [95,96]. Definite
diagnosis of Fabry disease is reached through the demonstration of decreased/absent
serum or leukocyte alpha galactosidase A activity or pathogenic variants in the GLA gene.
In addition, endomyocardial biopsy can identify histological alterations by showing the
accumulation of the degradation product of globotriaosylceramide in the sarcoplasm of
myocytes, forming concentric lamellar bodies [85,97]. Although the clinical response is
not always optimal, enzyme replacement therapy may ameliorate symptoms and renal
function, potentially reducing left ventricular hypertrophy, cardiac events, stroke, and
overall death [98–101].

4.2.2. Glycogen Storage Diseases

Glycogen storage diseases are a group of inherited genetic disorders that cause glyco-
gen to be improperly accumulated in the body. Although they are listed as cardiomy-
opathies that can also have a restrictive phenotype [7,51], patients affected with glycogen
storage diseases typically show a marked left ventricular hypertrophy and must be differen-
tiated mainly from HCM. This is particularly true for Danon disease (caused by deficiency
of lysosome-associated membrane protein 2-LAMP 2) in which the hypertrophy can be
so extreme as to reach 65 mm of left ventricular maximal wall thickness [102]. These
morphological findings correspond to increased QRS voltages and T wave abnormalities
at the ECG. Excess glycogen accumulates in cardiomyocytes and skeletal muscle fibers
leading to formation of vacuoles that stain positive with periodic Acid Schiff [85]. In
addition to skeletal and cardiac muscle involvement, mild to moderate mental retardation
is frequently observed.
PRKAG2 syndrome is another type of glycogen storage disease, whose presentation
includes skeletal myopathy, marked cardiac hypertrophy, arrhythmias, and conduction
defects [85]. Left ventricular hypertrophy is often progressive and associated with both
diastolic and systolic heart failure [103]. Maximal ventricular wall thickness varies widely
among different patients, ranging from normal values to over 40 mm [104–106]. A restric-
tive filling pattern, left ventricular outflow tract obstruction, and dilated progression are
leading causes of cardiac transplant or death [104,105,107]. Its key aspect is the association
with Wolff–Parkinson–White syndrome (characterized by a short PR interval, ventricu-
lar pre-excitation, and supraventricular tachycardia), together with possible advanced
atrioventricular blocks requiring pacemaker implantation. CMR patients with PRKAG2
syndrome may show LGE only in the advanced stages, together with high T1 values caused
by fibrosis [108].
The heart is also part of the clinical spectrum of Pompe disease (acid maltase deficiency
or glycogen storage disease type II) [57]. This disorder usually has an infantile onset,
producing massive cardiac hypertrophy in neonatal and pediatric ages, able to determine
left ventricular outflow tract obstruction. Diastolic dysfunction is generally present and
systolic dysfunction can be seen later on [57]. Adult-onset acid maltase deficiency is a
rare variant of the disease: as it seldom affects the heart, the cardiac phenotype of adults
with this condition is poorly characterized [109]. The morphology of the heart of patients
diagnosed with glycogen storage disease type III, also known as Cori disease, usually
mimics HCM but can show restrictive physiology [51,110].
J. Clin. Med. 2021, 10, 1954 12 of 17

5. Conclusions
HCM and primary RCM have a similar genetic background as they are both sarcomeric
cardiomyopathies, and significant phenotypic overlap can exist between them. Patients
with HCM and primary RCM may coexist in the same family and a new category of HCM
with restrictive physiology has been recently described. One hypothesis is that familiar
forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather
than a different genetic cardiomyopathy. To further complicate this delicate scenario some
infiltrative and storage diseases may show either a hypertrophic or restrictive phenotype
(HCM and primary RCM phenocopies) according to left ventricular wall thickness and
filling pattern. Establishing a correct diagnosis is of paramount importance for cascade
family screening and therapy.

Author Contributions: R.V., D.C., and C.C. contributed to the design of the work and R.V. drafted the
manuscript. A.A., C.B., A.C., A.Z., P.M., G.T., A.R., D.C., and C.C. critically revised the manuscript.
All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and
accuracy. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The authors wish to thank Erika Borsetto for assisting in the preparation of
the figures.
Conflicts of Interest: The authors declare no conflict of interest.

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