Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3849_Библиотеки_им_академика_М_И_Перельмана
.pdf
10 Hereditary Arrhythmias
https://t.me/medicina_free
Fig. 10.3 Peroposed Risk Stratication Scheme for ACA or SCD in LQT2*
227
increased risk of cardiovascular events (CEs) after the onset of
adolescence, and during the perimenopause period. The increase
in the risk of the perimenopause period was shown to be more
pronounced in women with LQTS2 genetic mutation [17].
In contrast, the risk of CEs in men is attenuated after the onset
of adolescence. The mechanisms leading to the different risk
between men and women has been attributed to the modulating
effects on the potassium channels associated with the cardiac
action potential.
Estrogen and progesterone were shown to have varying effects
on IKs and IKr currents. Testosterone, on the other hand increases
potassium channel currents, resulting in a shorter corrected QT
(QTc) in both animal and human studies.
More recently, the use of oral contraceptives was studied with
relation to the risk of CEs in female patients with LQTS.It was
found that progestin-only OC therapy is associated with increased
risk of CEs in women with congenital LQTS [18]. Concomitantly
beta-blocker therapy signicantly attenuates the risk of CEs dur-
228
https://t.me/medicina_free
ing progestin-only OC use. Importantly, the risk associated with
OC use is more pronounced in females with LQT2 gene mutations.
D. Huang et al.
Management
In general, the treatment of LQTS consists of lifestyle modications, medical therapy with beta-blockers, ICD and/or surgical
therapy. The ACC/AHA/ESC guidelines [19] and a recently published expert consensus statement [3] recommend lifestyle modications for all patients with a diagnosis of LQTS.Beta-blockers
are recommended as a Class I indication for all patients with a
clinical diagnosis of LQTS and as a Class IIa indication for
patients with a genetic diagnosis of LQTS who have a normal
QTc duration. Although there are limited data on the most effective dosage of beta-blockers, full dosing adjusted for age and
weight is recommended. Abrupt discontinuation of beta-blockers
should be avoided as this may cause exacerbation [3]. Implantation
of an ICD is recommended for LQTS patients who experience an
aborted cardiac arrest (class I indication) or for patients who had
syncope and/or VT despite beta-blockers therapy (class IIa indication). The recently published expert consensus statement [3] recommends performing left cardiac sympathetic denervation
(LCSD) in high-risk patients with a diagnosis of LQTS in whom
ICD therapy is contraindicated or refused and/or beta- blockers are
either not effective in preventing syncope/arrhythmias, not tolerated, or contraindicated (class IIa indication). In addition, the consensus statement has added that sodium channel blockers can be
useful, as add-on therapy, for LQT3 patients with a QTc >500ms
who shorten their QTc by >40ms following an acute oral sodium
channel blocker test (class IIa indication) [3].
Lifestyle Modications
The fact that patients with certain genotypes are more likely to
experience their events under well-dened circumstances may
provide insights into preventive measures. Patients with LQT1
10 Hereditary Arrhythmias
https://t.me/medicina_free
have most of their events during exercise. Therefore, they should
avoid strenuous exercise activity (particularly swimming) without
supervision, and those at intermediate or high risk should not
engage into competitive sports [3, 19]. Patients with LQT2 should
be advised to avoid unexpected auditory stimuli as their cardiac
events are predominantly associated with sudden arousal [17, 20].
Removal of loud noise stimuli at home and work such as elimination of alarm clocks, door bells and telephone ringing is usually
recommended. LQT3 patients mainly experience events during
sleep and at rest, and should be considered for a special intercom
system in the bedroom. All patients with LQTS should avoid
drugs known to prolong QT interval, or affect potassium and magnesium level. It is important to Identify and correct electrolyte
abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss [3].
229
Beta-Blockers
Beta-blocker therapy is the mainstay treatment of patients with
LQTS. The efcacy of this therapy in LQTS has been demonstrated in multiple studies. Moss etal. [21] have reported the efcacy of beta-blockers in 869 LQTS patients. Beta-blocker therapy
was associated with a signicant reduction in the rate of cardiac
events in probands (0.97± 1.42 to 0.31 ±0.86 events per year,
p < 0.001) and in affected family members (0.26 ± 0.84 to
0.15±0.69 events per year, p<0.001). In another study among
549 LQT1 and 422 LQT2 patients from the International LQTS
Registry, we have found that Beta-blocker therapy was associated
with a prominent risk-reduction in high-risk patients, including a
67% reduction (p=0.02) in LQT1 males and a 71% reduction
(p<0.001) in LQT2 females [22].
The protective effects of beta-blockers among LQTS patients
may also depend on mutation location. We have shown among
860 patients with genetically conrmed LQT1 that beta-blocker
therapy was associated with a signicant 88% reduction in the
risk of life-threatening cardiac events among LQT1 carriers of the
cytoplasmic loops (C-loop) missense mutations (p = 0.02),
whereas among LQT1 carriers of non-C-loop missense mutations
230
https://t.me/medicina_free
there was no signicant reduction in the risk for life threatening
cardiac events (HR 0.82, p = 0.68) [23]. It is known that the
C-loops play an important role in the sympathetic regulation of
the KCNQ1 channel [24]. Cellular expression studies have suggested that there is a combination of decrease in basal function
and altered adrenergic regulation of the IKs channel in patients
with C-loops missense mutations that may provide a potential
explanation why beta-blockers are particularly effective in
patients with this type of mutation [23].
The benet associated with the various beta-blocker subtypes
in the management of LQTS may not be equal. Two studies [22,
25] may suggest that metoprolol is less effective than Atenolol,
Nadolol or Propranolol among LQT1 and LQT2 patients.
Evidence suggests that treatment with nadolol results in the greatest risk reduction in the overall LQTS population, proven to be
effective mainly in LQT1 and LQT2 [2].
The clinical effect of the beta-blocker type may not be causally
related to its specic effect on the QTc interval. For example, propranolol may offer greater reductions in the QTc interval, but it is
suggested that its efcacy is mainly in patients with LQT1 [2].
Adherence to beta-blocker therapy is of utmost importance and
all patients must be counseled on it. A recent real-world study
regarding pharmacy dispensing data in patients with LQTS found
that over 50% of patients had suboptimal adherence to the prescribed beta-blocker therapy. Therefore, the risk reduction associated with optimal beta-blocker therapy adherence and dosing may
be much greater than what is reported.
Assessing sufcient beta-blocker effect during therapy can be
done with the demonstration of blunting of heart rate response
with exercise testing. The aim should not be for QTc shortening,
but a decrement of 15–20% during maximum exercise to demonstrate adequate effect and adherence.
D. Huang et al.
Adjunctive Medical Therapies
Mexiletine has been demonstrated to be efcacious in addition to
beta-blockers in the treatment of patients with LQTS. In fact,
patients with LQT3, who have a gain of function variant in there
10 Hereditary Arrhythmias
https://t.me/medicina_free
Nav1.5 sodium channel, mexiletine therapy resulted in a 60ms
reduction in QTc interval and reducing CEs. A small study showed
that adjunctive therapy with mexiletine to beta blockers may provide added therapeutic efcacy [2].
Other medications that have been used in small studies include
nicorandil and ranolazine through their effects on potentiation of
potassium channels and blockade of sodium channels, respectively. However, these therapies require further validation in
future large-scale clinical trials.
231
Potassium Supplementation
Potassium supplementation and spironolactone were proposed for
patients with LQT2 who exhibit mutation of the KCNH2 gene.
KCNH2 function is highly dependent on the extracellular potassium. It has been suggested that potassium administration will
increase serum potassium level and improve repolarization abnormalities. Two small studies have shown that potassium supplements and spironolactone are associated with a signicant
shortening of the QTc [26, 27]. Unfortunately, there are no data
that potassium supplements or spironolactone can decrease the
risk of cardiac events.
Sodium Channel Blockers
Over the last decade, sodium channel blockers such as mexiletine
and ecainide have been investigated as a potential treatment
option for patients with LQT3. Both Mexilitine [4] and Flecainide
[28–32] administration are associated with signicant shortening
of the QT interval among LQT3 patients.
Treatment Considerations During Pregnancy
Each stage of pregnancy poses a different risk in specic LQTS
population and understanding those risks as well as the safety of
treatment options is paramount to care for these patients. For
232
https://t.me/medicina_free
example, hyperemesis can be associated with the rst trimester. In
severe cases, this leads to poor absorption of medications and also
hypokalemia and hypomagnesemia. These women should be
monitored more closely with supplementations provided. It
should be noted that almost all antiemetic medications are QT
prolonging and should be avoided is possible. If used, ECG monitoring with frequent electrolyte checks should be done until
symptoms of hyperemesis subside [2, 33].
To date, continuation of beta-blockers is considered safe during pregnancy and reduces maternal risk especially in the postpartum period. It is important to explain that avoiding maternal
arrhythmic complications increases the chance of a healthy fetus
[33].
There is a broad safety data regarding propranolol during pregnancy given its pregnancy related hyperthyroidism indication and
non-selective mechanism. However, high-risk LQTS patients usually may continue nadolol without signicant issues.
In the largest study on pregnancy including patients with
LQTS, the pregnancy period was associated with fewer events
when compared to the pre-pregnancy period. The postpartum
period is considered a proarrhythmic trigger in long QT syndrome, especially in type 2, which poses the greatest risk of
arrhythmias. Importantly, the risk remains elevated for a minimum of 9 months postpartum especially for the type 2 patient
population. During this postpartum period, propranolol is a god
option as it can be taken while breastfeeding, while nadolol is
generally not recommended but often continued if women have
been stable on it during pregnancy [33].
D. Huang et al.
Device Therapies
In patients with LQTS and a history of cardiac arrest, there is a
clear indication for ICD insertion for secondary prevention. The
decision for primary prevention ICD is more nuanced and should
take into consideration the risk of sustaining a life-threatening
ventricular tachyarrhythmia vs the risk of device related complications. These device related complications include inappropriate
10 Hereditary Arrhythmias
https://t.me/medicina_free
shocks, device infection, lead malfunction, and psychological
consequences among others [2].
The intravenous dual-chamber ICD may be more advantageous than a subcutaneous ICD in LQTS patients for several reasons. First, there is more experience with the intravenous ICD
among these patients. Second, the atrial overdrive pacing function
may offer benets for treatment of acute ventricular arrhythmias
or for their prevention in pause dependent QT prolongation [2].
A pacemaker therapy without an ICD can be considered in certain patients including those with pause-dependent or bradycardiarelated TdP as pacing may improve QT changes associated with
heart rate variability. A pacemaker may also provide additional
benet in those patients not able to tolerate adequate doses of
beta-blocker therapy [2].
233
Left Cardiac Sympathetic Denervation
This mode of therapy can reduce the number of CEs in patients
who are already taking beta-blockers or in those who have failed
beta-blocker therapy [2].
Technical Aspects
QTc Values The normal and prolonged QTc values depend on age
and gender. Suggested QTc values for diagnosing QTc prolongation are: QTc >460ms during childhood (ages 1–15years), QTc
>450ms for adult males, and QTc >470ms for adult females [32].
QT and QTc Measurement The QT interval should be determined as a mean value derived from at least 3–5 cardiac cycles,
and is measured from the beginning of the QRS complex to the
end of the T wave.
The QT measurement should be made in leads II and V5 or V6,
with the longest value being used. The main difculty lies when
there are T and U waves that are close together. When T-wave
deections of a near-equal amplitude result in a biphasic T wave,
234
https://t.me/medicina_free
the QT interval is measured to the time of nal return to baseline.
If a second low amplitude repolarization wave interrupts the terminal portion of the T wave, it is difcult to determine whether
the second deection is a biphasic T wave or an early-occurring U
wave. In such cases, it is best to record both the QT (measured at
the end of the rst deection) and the QTU (measured at the end
of the second deection) intervals [5].
The Bazett formula is widely used to correct the QT interval
for heart rate (QTc); QTc equals QT divided by the square root of
the R-R interval (all intervals should be measured in seconds).
Epinephrine QT Stress Test This provocative test may aid in
unmasking individuals with concealed LQT1 [6]. There are two
available protocols: by bolus infusion (Shimizu protocol) or an
incremental, escalating infusion (Mayo protocol). According to
the Mayo protocol, [6] after 10min of rest, 12 lead ECG recording speed was set at 50mm/s, baseline parameters were obtained
(including QT and QTc), and then an infusion of epinephrine was
initiated at 0.025μg/kg/min. After 10minutes of the infusion, the
measurements were repeated. The epinephrine infusion was then
increased sequentially to 0.05, and 0.1μg/kg/min, and the measurements were repeated 5minutes after each dose increase. The
epinephrine infusion was then discontinued, and measurements
were obtained 5 and 10min afterwards. A paradoxical response
characterized by uncorrected QT lengthening (ΔQT ≥ 30 ms)
rather than expected shortening appears diagnostic for LQT1
(with a sensitivity and specicity of 92% and 86%, respectively).
D. Huang et al.
Brugada Syndrome
Incidence andEtiology
Brugada syndrome is another familial disorder with structurally
normal heart that involves mutations in genes encoding myocyte
ion channels. Brugada syndrome is characterized by a specic
ECG pattern of coved-type ST-segment elevation in the right precordial leads (V1 through V3) accompanied by a susceptibility to
10 Hereditary Arrhythmias
https://t.me/medicina_free
polymorphic VT and SCD [34]. Brugada syndrome prevalence
has been estimated at 1 per 2000 people worldwide. The prevalence is higher in Asian and Southeast Asian countries, especially
Thailand, Philippines and Japan [35, 36].
Brugada syndrome is typically inherited through an autosomal
dominant mode of transmission. To date, 12 Brugada syndromeassociated genes have been reported [37], with all mutations leading to either a decrease in the inward sodium or calcium current or
an increase in outward potassium current.
Approximately 25% of cases of Brugada syndrome result from
mutations in the SCN5A gene that encodes for the α subunit of the
cardiac sodium channel. Overall, the genetic cause has been identied for only 30% of clinically diagnosed Brugada syndrome
patients.
235
Clinical Presentation
Overall there is a male predominance (about 90% of cases). The
rst symptoms typically occur in the third to fourth decade of
life. These symptoms may range from syncope to SCD. That
being said, the majority of newly diagnosed patients are asymptomatic (about 64%) or have a history of syncope (30%). Only
about 6% of patients present with a cardiac arrest. Conditions
that may bring about type-1 Brugada pattern include electrolyte
imbalances, hyperthermia, fever, and sodium channel-blocking
drugs [38].
Diagnosis
Three ECG patterns associated with Brugada syndrome were
described.
Type 1 is characterized by a J point elevation ≥2mm (0.2mV),
a coved ST-segment elevation followed by a negative T wave.
This ECG pattern is diagnostic of Brugada syndrome. Type 2 has
a J point elevation ≥2mm, ST-segment elevation has a saddleback appearance, and then either a positive or biphasic T wave.
236
https://t.me/medicina_free
D. Huang et al.
Type 3 has either a saddleback or coved appearance with a J point
elevation <2mm, and an ST-segment elevation of <1mm.
Type 2 and type 3 ECG are not diagnostic of the Brugada
syndrome.
The most recent expert consensus statement recommends the
following criteria in diagnosing Brugada Syndrome:
1. A spontaneous type 1 (coved type) BrS-ECG as described
above
2. Type 1 Brugada syndrome unmasked by sodium channel
blockers or fever only when having a type 2 or type 3 ECG at
baseline and when accompanied by at least one additional criterion from the ‘Shanghai Score System’. This score system
takes into account ECG patterns, clinical history, family history, and genetic testing in the prediction of a true Brugada
Syndrome diagnosis.
It is important to exclude phenocopies which are other conditions
that may explain a coved-type ECG. If the baseline ECG lacks the
spontaneous type 1 Brugada pattern, then sodium channel blocker
challenge should only be performed if the clinical suspicion
remains high. This is because there is an estimated rate of 5%
positive tests in healthy subjects and the consequences of treatment can be life-changing. These can include patients who have
had a cardiac arrest or arrhythmias while febrile, patients with a
family history of Brugada Syndrome, or unexplained SCD.
Genetics ofBrugada Syndrome
Mutations in the SCN5A gene encoding the cardiac sodium channel have been identied in patients with Brugada Syndrome.
These lead to a dysfunctional sodium channel at the cell membrane, resulting in a decreased sodium current. Among patients
with these mutations there is a broad variability of symptom
severity and age of onset leading to variable disease expression.
There is also incomplete penetrance as some family members
who have the same mutation may be asymptomatic. Conversely,
patients with clinical Brugada Syndrome who have this mutation
have family members who are not carriers of the same mutation
Соседние файлы в папке Библиотека им академика М.И. Перельмана