Restrictive cardiomyopathy

Jens Mogensena and Eloisa Arbustinib

a
Department of Cardiology, Skejby University Hospital,
Brendstrupgaardsvej, Aarhus N, Denmark and
b
Academic Hospital, IRCCS Foundation Policlinico San
Matteo, Pavia, Italy

Correspondence to Jens Mogensen, MD, PhD,

Department of Cardiology, Skejby University Hospital,
Brendstrupgaardsvej, 8200 Aarhus N, Denmark
Tel: +45 89 49 61 99; fax: +45 89 49 60 02;
e-mail: jens.mogensen@dadlnet.dk
Current Opinion in Cardiology 2009,
24:214220

Purpose of review
Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease characterized
by impaired filling of the ventricles in the presence of normal wall thickness and systolic
function. Most affected individuals have severe signs and symptoms of heart failure.
A large number die shortly after diagnosis unless they receive a cardiac transplant.
Controversy has existed about the exact definition of the condition and diagnostic
criteria that will be discussed along with an update on recent findings.
Recent findings
Previously, RCM was believed to be of idiopathic origin unless otherwise associated
with inflammatory, infiltrative or systemic disease. Recent investigations have shown
that the condition may be caused by mutations in sarcomeric disease genes and even
may coexist with hypertrophic cardiomyopathy in the same family. However, most
sarcomeric RCM mutations appear to be de novo and associated with a severe disease
expression and an early onset.
Summary
Recent reports suggest that mutations in sarcomeric contractile protein genes are
not uncommon in RCM. These findings imply that RCM may be hereditary, and that
clinical assessment of relatives should be considered in addition to genetic
investigations when systemic disease has been excluded. Identification and risk
stratification of affected relatives is important to avoid adverse disease complications
and diminish the rate of sudden death.
Keywords
genetic investigations, inheritance, restrictive cardiomyopathy
Curr Opin Cardiol 24:214220
2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
0268-4705

Introduction
Restrictive cardiomyopathy (RCM) is characterized by
increased stiffness of the ventricles leading to compromised diastolic filling with preserved systolic function.
These changes may develop in association with local
inflammatory or systemic, infiltrative or storage disease
(Fig. 1) [1]. Usually, patients develop severe symptoms of
heart failure over a short period of time, and the majority
die within a few years following diagnosis unless they
receive a cardiac transplant [2]. The results of recent
molecular genetic investigations have revealed that
a substantial proportion of RCM without associated
systemic disease is caused by mutations in sarcomeric
disease genes that have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy
(DCM) and noncompaction cardiomyopathy [35,6].
Controversy exists on how to define the condition
because restrictive filling patterns of the ventricles occur
in a wide range of different diseases [79]. It is the
purpose of this review to demonstrate that a variety of
0268-4705 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

myocardial and systemic diseases are associated with

RCM. Therefore, the definition of RCM should be
descriptive rather than categorical and reflect that many
conditions may ultimately lead to RCM.

Clinical characteristics
Adult RCM patients present with dyspnea, fatigue and
limited exercise capacity. They may experience palpitation accompanied by dizziness due to supraventricular
arrhythmia (SVT). Thromboembolic complications are
common and may be the initial presentation of the
condition. In children, RCM may present with failure
to thrive, fatigue and even syncope [8,9]. In advanced
cases, patients develop raised jugular venous pressures,
peripheral edema, liver enlargement and ascites. Chest
radiograph usually shows a normal-sized heart with
enlarged atria and variable degrees of pulmonary congestion. The ECG exhibits large P waves indicating
biatrial enlargement accompanied by various ST segment
and T wave abnormalities (Fig. 2b). Echocardiography
typically reveals biatrial enlargement, a normal or slightly
DOI:10.1097/HCO.0b013e32832a1d2e

Restrictive cardiomyopathy Mogensen and Arbustini 215

Figure 1 Restrictive cardiomyopathy

Restrictive
cardiomyopathy

Inflammatory

Infiltrative

Storage

Idiopathic

Endomyocardial
fibrosis

Amyloidosis

Hemochromatosis

Loeffler
cardiomyopathy

Sarcoidosis

Glycogen
storage disease

Postirradiation
therapy

Fabry disease

Patients need to be assessed in relation to familial involvement and the potential genetic basis. Adapted from [1].

impaired systolic function and mitral inflow Doppler

velocities indicative of severe diastolic dysfunction
(Fig. 2a). These include increased ratio of early diastolic
filling to atrial filling, decreased E-deceleration time and
decreased isovolumic relaxation time (IVRT) (Fig. 3).
Invasive pressure measurements within the ventricles
during cardiac catheterization are characterized by an
early diastolic dip quickly followed by a plateau, also
called the square-root sign. Usually, the diastolic pressure of both ventricles is elevated with the highest
plateau being in the left ventricle [2]. However, when
diagnosing RCM, it is important to realize that pressure
measurements obtained during cardiac catheterization
as well as Doppler velocities vary according to preload,
which in turn is highly dependent on the current medication of individual patients. For instance, aggressive
diuretic therapy will tend to normalize filling pressures
and diastolic volumes. Furthermore, pressures and velocities also vary in response to heart rate and rhythm [7].

Diagnosis

RCM in patients with mild systolic dysfunction or mild

left ventricular hypertrophy or both, the specific values
for Doppler velocities and diastolic volumes and whether
systemic diseases such as amyloidosis and glycogen
storage diseases should be classified as RCM [7,10].
Recently, a working group of the European Society
of Cardiology (ESC) proposed revised classification of
cardiomyopathies reflecting the clinical disease expression of the conditions focusing on ventricular morphology
and function and the familial/genetic background [11].
Specifically, the classification characterizes cardiomyopathies in relation to the familial background. In this context, RCM is defined as a condition presenting with
restrictive ventricular physiology in the presence of
normal or reduced diastolic volumes and normal ventricular wall thickness in the absence of ischemic heart
disease, hypertension, valvular heart disease and congenital heart disease. This broad definition should help
physicians to identify the condition and consider further
diagnostic investigations to reveal the cause that may
include cardiac biopsies, family screening and genetic
investigations.

It has been difficult to obtain consensus about uniform

diagnostic criteria of RCM. From a historical perspective,
there has been general agreement that RCM should be
considered in patients presenting with heart failure in
the presence of a nondilated, nonhypertrophic left ventricle with preserved contractility but abnormal diastolic
function. There is uncertainty regarding the diagnosis of

Differentiation of RCM from constrictive pericarditis is

important, as patients suffering from the latter condition
may recover completely following surgical removal of the
fibrotic pericardium. However, the distinction between
the two conditions may be difficult. Noninvasive realtime
imaging with echo Doppler and respirometry provides

216 Molecular genetics

Figure 2 Restrictive cardiomyopathy

Clinical characteristics of restrictive cardiomyopathy in a 19-year-old male who was diagnosed at the age of 16 years following a stroke as previously
reported [7]. (a) Apical four-chamber echocardiogram in systole with marked biatrial dilatation, normal-sized ventricles and normal wall thickness.
(b) Twelve-lead ECG in sinus rhythm with prominent P waves, T wave inversion and incomplete right bundle branch block. (c) Microscopy of heart
tissue obtained postmortem with myocyte hypertrophy, abundant fibrosis and myofibrillar disarray characteristic of the histological findings in HCM
(hematoxylineosin staining, x40). aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right; HCM, hypertrophic
cardiomyopathy. Part (a) adapted from [3]. Parts (b) and (c) reproduced from [3].

the mainstay of diagnosis. Patients with restriction will

not have sufficient respiratory variation. Cardiac magnetic resonance and computed tomography (CT) may
be useful to assess pericardial thickness, whereas MRI
with late enhancement may facilitate diagnosis of infiltrative myocardial disease, for example, amyloidosis.
During invasive investigation, it is possible to obtain
simultaneous pressure measurements in the ventricles,
and both conditions are characterized by rapid early
diastolic filling with diastolic dip and plateau waveform.
There may be a pressure difference between left
ventricular end-diastolic pressure (LVEDP) and right
ventricular end-diastolic pressure (RVEDP) in RCM,
which is considered significant if diastolic pressure is

more than 57 mmHg, in contrast to constrictive pericarditis, in which the pressures tend to be equal in both
ventricles. Nonetheless, no technique is totally reliable,
and in some patients it is necessary to perform a diagnostic pericardiectomy [2,7,12,13].

Outcome
RCM carries a poor prognosis, particularly in children,
despite optimal medical treatment. Several studies
[14,15] have reported that 66100% die or receive a
cardiac transplant within a few years of diagnosis. In one
study of 18 RCM children, five died suddenly without
signs of heart failure. However, they had severe angina

Restrictive cardiomyopathy Mogensen and Arbustini 217

Figure 3 Doppler velocities in restrictive cardiomyopathy

Typical restrictive Doppler findings including increased E to A ratio (2.1), decreased E-deceleration time (90 ms) and decreased isovolumetric
relaxation time (40 ms). A, atrial filling; E, early diastolic filling.

and ECG evidence of ischemia. Four hearts of children

who died suddenly were available for autopsy and revealed
acute myocardial infarcts, subendocardial ischemic necrosis or chronic ischemic scarring, despite normal appearance
of their coronary arteries. These findings led the authors to
suggest that pediatric patients with RCM represent a
population of children who are at high risk for ischemiarelated complications and death in addition to heart failure.
In adults, two studies [16,17] have reported that 3244%
suffered a cardiovascular-related death within 5 years
following diagnosis. The outcome is highly correlated to
symptoms and signs of heart failure. Embolic stroke is a
common complication as a consequence of large atria
and SVT. Therefore, prophylactic anticoagulant therapy
should be considered in all RCM patients with enlarged
atria even before SVT has developed.

Familial restrictive cardiomyopathy

associated with sarcomeric gene mutations
In 1992, Feld and Caspi [18] reported a family with a
mixed appearance of RCM and HCM. The cardiac
morphology of a deceased individual with RCM showed
typical features of HCM with myocyte disarray. Angelini
et al. [19] reported similar histomorphological features of
seven patients with a clinical diagnosis of RCM and
suggested that RCM and HCM may represent two
different phenotypes of the same basic sarcomeric disease, although no genetic investigations were performed.
We investigated a large family in which the proband and
two additional individuals were diagnosed with RCM,

nine individuals had clinical features of HCM and 12

individuals died suddenly. Linkage analysis for selected
sarcomeric contractile protein genes identified troponin
I [troponin I (TNNI3)] as the likely disease gene [3].
Subsequent mutation analysis revealed a missense mutation, which segregated with the disease in the family (lod
score: 4.8). To elucidate whether TNNI3 mutations were
common in RCM, mutation analysis was performed in
nine unrelated RCM patients with unexplained restrictive filling patterns, gross atrial dilatation, normal systolic
function and normal wall thickness. Histology of heart
tissue from several individuals showed myofibril disarray
characteristic of HCM (Fig. 2c). TNNI3 mutations were
identified in seven of 10 patients including the index
family of the study. Two of the mutations identified in
young individuals were de-novo mutations. All mutations
were novel missense mutations and appeared in conserved and functionally important domains of the gene.
We concluded that mutations in cardiac troponin I were
responsible for the development of RCM in a significant proportion of patients diagnosed with RCM. Additional TNNI3 mutations have been reported in RCM,
as well as mutations in other sarcomeric genes including troponin T (TNNT2), b-myosin heavy chain (MYH7)
and a-cardiac actin (ACTC) [15,2022]. Most of the
mutations reported appeared de novo with a severe disease
expression and onset of symptoms in childhood leading to
premature death or cardiac transplantation shortly after
diagnosis. These findings imply that RCM is part of
the clinical expression of hereditary sarcomeric contractile protein disease, and familial evaluation should be

218 Molecular genetics

Figure 4 Cardiac amyloidosis

considered whenever an individual has been diagnosed

with RCM.

Familial restrictive cardiomyopathy,

atrioventricular block and desmin
accumulation
Desmin-related myopathies are very rare disorders
characterized by intracytoplasmatic accumulation of desmin caused by mutations in the gene for either desmin
(DES) or a-B-crystallin (CRYAB). Diagnosis requires
ultrastructural investigation and immunohistochemistry
of cardiac or skeletal muscle biopsy to reveal desmin
deposits [23]. The disease expression may involve
skeletal muscle only, affect both cardiac and skeletal
muscle simultaneously or have an isolated impact on
the heart [2427]. Very few families have been reported
with isolated RCM and cardiac-specific accumulation of
desmin. In one large four-generation family, no disease
gene was identified, whereas another report identified
four independent individuals with RCM, atrioventricular
block and mutations of the DES gene [23,28]. Genetic
investigations and clinical assessment of relatives
revealed one de-novo mutation, one mutation with recessive inheritance and two dominant mutations with a total
number of three affected relatives. Penetrance was 100%,
and all but one had advanced atrioventricular block.
Recognizing that this disease expression is extremely
rare, the authors suggested that desmin accumulation
might be considered in patients presenting with RCM
and atrioventricular block.

Cardiac amyloidosis
By tradition, cardiac amyloidosis has been classified as a
RCM, as deposits of amyloid within the heart typically
result in restrictive filling patterns [10,11].
However, this condition is also characterized by increased
ventricular wall thickness and impaired systolic function. Echocardiography often reveals a remarkable homogeneous granular sparkling of the myocardium, and valves
are often thickened due to amyloid infiltration. In addition,
the ECG of patients with cardiac amyloidosis often shows
low voltage in standard leads. Cardiac biopsies show
typical features of amyloid deposits (Fig. 4ac). A variety
of diseases are associated with sporadic occurrence of
Figure 4 (continued)

Clinical characteristics of a 46-year-old male who was diagnosed with

cardiac amyloidosis at the age of 42 years because of heart failure
symptoms. (a) Apical four-chamber view in systole with biatrial dilatation,
normal-sized ventricles and significant thickening of ventricular walls that

appears bright and sparkling. (b) Twelve-lead ECG in sinus rhythm with
low voltage in standard leads. (c) Microscopy of cardiac biopsies stained
with hematoxylineosin showing extensive infiltration of amyloid between
myocytes (x40). The small picture inserted shows cardiac tissue from the
same patient stained with Congo red, which defines amyloid deposits by
its green refringence under polarized light. aVF, augmented vector foot;
aVL, augmented vector left; aVR, augmented vector right.

Restrictive cardiomyopathy Mogensen and Arbustini 219

cardiac amyloidosis, whereas hereditary appearances

most often are caused by mutations in the genes for
transthyretin and apolipoprotein A1 [29,30].

Other rare familial diseases associated with

restrictive cardiomyopathy
Hemochromatosis is an autosomal recessive disorder
leading to iron deposition in multiple organs resulting
in widespread damage. Although clinical disease expression in many cases is unpredictable, most patients present
with a variety of symptoms from different organ systems,
whereas only few patients have isolated cardiac manifestations and very rarely RCM [29]. AndersonFabrys
disease is an X-linked lysosomal storage disorder caused
by mutations in the gene for a-galactosidase A (GLA).
Glycosphingolipids accumulate in multiple organs and
cause substantial morbidity and mortality, especially in
men. In women, isolated affection of the heart is more
frequent than in men, and affected women most often
present with symptoms late in life. Typical echocardiographic findings include left ventricular hypertrophy,
modest diastolic filling abnormalities and thickening
of the valves [3133]. RCM in the context of Fabrys
disease with normal ventricular wall thickness is extremely rare [34]. The same seems to be the case with a
variety of rare hereditary glycogen storage diseases exhibiting different modes of transmission.

Nonfamilial restrictive cardiomyopathy

Sporadic RCM may be diagnosed in patients affected by
systemic diseases including scleroderma and sarcoidosis
[29]. Patients who previously have undergone radiotherapy of the chest, as in Hodgkins disease, have an
increased risk of developing myocardial and endocardial
fibrosis many years later leading to RCM. Restrictive
ventricular physiology can also be caused by endocardial
fibrosis in association with hypereosinophilic syndromes
or induced by exposure to various drugs and parasitic
infections [30].

Conclusion
RCM is an uncommon condition with a poor outcome
unless patients receive a cardiac transplant. RCM is
generally seen in association with local inflammatory or
systemic diseases. The finding of TNNI3 mutations in a
substantial proportion of patients fulfilling diagnostic
criteria of idiopathic RCM suggested a causal relationship between gene abnormality and disease. This has
prompted genetic investigations of other RCM patients
and confirmed that RCM in many instances is part of the
clinical expression of sarcomeric contractile protein disease. De-novo mutations appear to be prevalent findings
especially in children and young adults, suggesting that
they are associated with a more severe disease expression

and early onset in comparison with mutations that have

been inherited through many generations.
As RCM, HCM, DCM and even noncompaction cardiomyopathy may be caused by mutations in the same
genes, previous perceptions of cardiomyopathies as separate and distinct clinical and pathophysiological entities
are difficult to sustain. It is important to realize that
transitional forms of the conditions frequently appear
even within the same family affected by the same
mutation. Therefore, the diagnosis of any condition likely
to be a cardiomyopathy should lead to family screening
for a potential hereditary disorder. Identification and risk
stratification of affected relatives is important to avoid
adverse disease complications and diminish the rate of
sudden death.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 260261).
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