Introduction
Hypertrophic cardiomyopathy (HCM) is an inherited autosomal-dominant disease with
a heterogeneous clinical presentation and natural history
1
, and is a frequent cause of sudden cardiac death (SCD) in young people
2–4
. It is associated with mutations in genes coding for sarcomere proteins
5–7
. In the literature, debate surrounds the genotype-phenotype correlation of individual
mutations
7,8
concerning establishing a prognosis according to the mutation present, which could
help stratify the disease and allow appropriate genetic counselling to families.
In an adult, HCM is defined by a wall thickness ≥15 mm in one or more left ventricular
(LV) myocardial segments—as measured by any imaging technique (echocardiography, cardiac
magnetic resonance imaging (CMR) or computed tomography)—that is not explained solely
by loading conditions
9
, but there are cases of HCM with thicknesses of less than 15 mm and even cases without
hypertrophy, all documented by the presence of disarray in the histopathological study
of the heart, given that they are also cases with high arrhythmic risk and therefore
SCD.
In the latest guidelines of the European Society of Cardiology
9
this circumstance is scarcely mentioned. Only the following text refers to it specifically:
“Genetic and non-genetic disorders can present with lesser degrees of wall thickening
(13–14 mm)”. It is also mentioned in the section on Diagnostic Challenges: “Common
diagnostic challenges include the following:
•
Presentation in the late phase of the disease with a dilated and/or hypokinetic left
ventricle and LV wall thinning
•
Physiological hypertrophy caused by intense athletic training
•
Patients with co-existent pathologies
•
Isolated basal septal hypertrophy in elderly people”
In children, the diagnosis of HCM requires an LV wall thickness more than two standard
deviations greater than the predicted mean (z-score >2, where a z-score is defined
as the number of standard deviations from the population mean).
Therefore, cases with very little hypertrophy and a lot of fibrosis or disarray do
not appear in the clinical guidelines, and there is no reference to their management
and prognosis.
10.7717/gcsp.201826/table-1
Table 1
Studies published on survival in TNNT2 gene mutations.
Studies
Number of families
Number of patients
Number of cardiac deaths
Number of sudden deaths
Mutation
Watkins
9
1995
11
112
50
39
Ile79AsnArg92GlnPhe110IleΔGlu160Glu163LysGlu244AspIntron 15 G>AArg278Cys
Nakajima-Tanaguchi22 1997
1
4
2
2
Ala104Val
Moolman
11
1997
2
22
7
7
Arg92Trp
Anan
17
1998
6
18
2
2
Phe110Ile
Torriceli
18
2003
5
10
0
0
Phe110IleArg130CysΔGlu160Arg92GlnArg278Cys
Pasquale23 2012
20
92
¿?
7
Arg278Cys Arg92LeuArg92TrpΔGlu163IVS15+1G>AAla104Val, Arg278HisArg92Gln Arg94LeuGlu163LysGlu83LysIle79Asn
Ripoll-Vera 2016
21
54
11
6
Arg92GlnArg92TrpArg286HisArg278CysArg94HisIle221Thr
10.7717/gcsp.201826/fig-1
Figure 1.
Free survival of sudden cardiac death, including patients with recovered SCD and patients
with appropriate ICD therapies, depending on the genetic result.
10.7717/gcsp.201826/fig-2
Figure 2.
Clinical case of a family: the proband is a 19 years old man with a SCD.
His mother had an HCM and is carrier of a mutation in TNNT gene (Arg92Trp). The pedigree
shows that there are also 2 sisters and 1 brother carrying the same mutation. Images
from the youngest sister are shown: a pathological electrocardiogram with ST elevation
in right precordial leads and negatives T waves in lateral and inferior wall, and
a TTE and CMR showing a normal LV wall thickness, except for the posterior wall (mild
hypertrophy) and a severe amount of fibrosis in this localization (red arrows).
Mutations in the troponin T gene (TNNT2) were described years ago in several publications
with few families, and researchers postulated a high prevalence of SCD in young carriers
5,6,10,11
, who, in addition, had a phenotype of mild left ventricular hypertrophy
6,12
.
The first cases were described in 1990 by McKenna et al.
13
, and the first mutation in TNNT2 gene in 1999 by the same group
14
. Mutations in TNNT2 represent around 5% of cases of HCM. They have been described
as associated with moderate or mild hypertrophy with a poor prognosis due to a high
risk of SCD, even in the absence of hypertrophy, with early expression in adolescence,
based mainly on the study by Watkins et al.
10
, in which 11 families with 8 different mutations were described.
More recently, two series with a greater number of families have been published
15,16
(Pasquale et al., 2012, 20 families and 12 mutations, and Ripoll-Vera et al., 2016,
21 families and 6 different mutations) (Table 1). In these last series it was found
that in the TNNT2 gene HCM up to 19% the ECG is normal and in 23% the transthoracic
echocardiography (TTE) does not show hypertrophy. On the contrary, up to 24–48% non-sustained
ventricular tachycardia is documented. However, we must differentiate which mutations
we are talking about. Not all mutations in the TNNT2 gene have a poor prognosis (Figure
1).
The Arg92Gln mutation is the most studied, it can manifest as HCM with little hypertrophy,
but also as dilated cardiomyopathy, especially at older ages. The high burden of SCD
is a constant in these families. Of 15 cases documented in 10 families, SCD was the
first manifestation of the disease in all, at an average age of 21 years (range 11–42)
and with an average myocardial thickness of 14.6 ± 5.2 mm. Up to 40% of patients required
the implantation of an implantable cardiac defibrillator (ICD), either for primary
or secondary prevention. The Arg94Leu mutation, like Arg94Cys and Arg94His, that affect
the same residue, also behave with a certain malignancy
17
. Microscopic evaluation in some studies in carriers of these TNNT2 mutations indicate
that cause less hypertrophy and fibrosis than other sarcomeric mutations, but more
disarray. This may be the substrate that explains the high arrhythmic risk
18
.
Conversely, other mutations such as Arg278Cys or Arg286His, also in the TNNT2 gene,
have a much more benign course
16
.
The diagnosis of these patients is therefore complex, and in some cases an ECG and
a TTE will not be enough. CMR has shown its usefulness against TTE in the detection
of mild hypertrophies or in the evaluation of worst viewed segments by TTE
19
. Even in those cases with little or no hypertrophy, the presence of late gadolinium
enhancement is a risk marker for SCD in these patients. It has been shown that in
these cases, where there is an absence of the classic risk factors of SCD in HCM,
the presence of more than 15–20% of fibrosis is a strong and independent marker of
outcomes. Even Maron et al.
20
proposed an algorithm in which it is emphasized that a HCM with extensive fibrosis
and absence of conventional risk factors of SCD, an ICD should be implanted as primary
prevention.
Recently, new techniques have been incorporated in CMR such as T1 mapping and quantification
of extracellular volume (ECV), which seem to have a manifest utility as an early marker
of the disease, even when fibrosis has not yet appeared (Figure 2).
Conclusions
a)
The current definition of HCM does not cover all possible phenotypes, because HCM
with little or even “no hypertrophy” exists and can have a very bad prognosis, with
SCD at young ages, being very frequently the first manifestation of the disease.
b)
In histopathology, a lot of disarray is noticeable in this particular phenotype.
c)
It is especially related to some mutations in TNNT2. The clinical and prognostic profiles
depended greatly on the specific mutation.
d)
A common factor is usually the presence of family history of SCD.
e)
To stratify the risk of the carriers, we can not trust only the ESC risk score or
the classic American criteria.
f)
CMR is essential to identify hypertrophy in segments that are more “hidden” to TTE
and to evaluate the presence of fibrosis, which is a very important risk marker in
these patients and can help us define which patients need an ICD.
g)
Investigation of the genotype-phenotype correlation in HCM remains a challenge.
h)
Overall, these findings have important implications for the clinical and genetic study
of families with cardiomyopathy, above all the findings of some TNNT2 mutations, which,
given its demonstrated malignancy, should cause a change in the management of individuals
in SCD prevention.