Atrial Fibrillation in Hypertrophic Obstructive Cardiomyopathy - Antiarrhythmics,
ablation and more!
Malasana MD1, John D. Day MD2, T. Jared Bunch MD2
1Department of Internal Medicine, University of Utah
School of Medicine, Salt Lake City, Utah.
2Intermountain Heart Rhythm Specialists, Department of
Cardiology, Intermountain Medical Center, Murray, Utah.
Address for correspondence: T. Jared Bunch, M.D, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510, Murray, Utah, 84107.
cardiomyopathy (HCM) is a genetic disease of the cardiac sarcomere with an autosomal
dominant pattern of inheritance. Patients with
HCM are at high risk of developing atrial fibrillation (AF) particularly in the
setting of advanced diastolic dysfunction and left atrial enlargement. AF is a
marker of increased mortality and morbidity and results in a significant
reduction in quality of life. Antiarrhythmic medications improve symptoms and
reduce AF recurrence, but few are safe and there exists little data to guide
their long-term use in HCM. Non-pharmacologic approaches have emerged and have
equal or greater efficacy than pharmacologic approaches. Although these
approaches are promising, the long-term impact on atrial function needs to be
carefully studied as it may impact quality of life in patients that age in the
setting of a progressive diastolic disease disorder. Nonetheless, with the
significant impact of AF in HCM, rhythm control strategies are often required.
The understanding of rhythm control strategies in HCM, an often rapidly
progressive diastolic dysfunction disorder, may provide insight in how to treat
the much more prevalent AF patient with hypertensive cardiomyopathy.
Regardless of treatment strategy (rhythm or rate control) patients are a
moderate to high risk of thromboembolism and until data are available to suggest
otherwise require long-term warfarin anticoagulation.
cardiomyopathy (HCM) is a genetic disease of the cardiac sarcomere with an
autosomal dominant pattern of inheritance. There are
more than 450 familial hypertrophic
cardiomyopathy- causing mutations identified in 20 genes, that encode cardiac
isoforms of sarcomere and sarcomere-related gene products .
Of these, cardiac-myosin binding protein-C is the most commonly affected gene
(15–50%) [2, 3, 4];
β-MHC is the next most common (13–25%) [2, 3,
5], followed by mutations in cardiac troponin isoforms I and
T(4–15%) [2, 5, 6, 7, 8, 9].
The genetic defects involved in HCM lead to myofibril
disarray and cause ventricular hypertrophy over time. Although significant
phenotypic variation exists, the most common form of HCM involves hypertrophy
of the septum extending to the outflow tract. In approximately 25% of patients
the muscle thickening is evenly distributed throughout the ventricle and in
approximately 10%, myocardial thickening is predominantly at the apex of the
heart . The myofibril disarray present in the septum and even in other
distinct areas of the myocardium that may or may not be hypertrophied but can
contribute to ventricular arrhythmogenic substrate and/or diastolic dysfunction
and heart failure symptoms.
In patients with HCM, dynamic left ventricular
outflow tract obstruction is an important pathophysiologic feature that
distinguishes obstructive HCM from nonobstructive disease and is closely
correlated with long-term adverse outcomes . Despite
structural impairment, outflow obstruction through the Venturi phenomenon
during systole can also result in systolic anterior motion of the mitral valve
resulting in mitral valve regurgitation, valve leaflet fibrosis, and valve
degeneration [12, 13]. The combined state
of structural and valvular heart disease can result in heart failure symptoms,
ventricular arrhythmias, apical thrombi, and premature death [14,
15, 16, 17, 18]. In patients with the acquisition of other disease states
such as coronary artery disease the pathologic process may be accelerated .
The clinical manifestations of HCM vary considerably resultant from a
broad spectrum of morphologic and hemodynamic abnormalities (Figure
1). Common symptoms are dyspnea on exertion, chest pain, orthopnea and
paroxysmal nocturnal dyspnea, palpitations, fatigure, postural lightheadedness,
presyncope and/or syncope. Most patients are diagnosed with HCM because of
routine screening due to a family history of HCM. Overtime, asymptomatic
patients can become symptomatic with 25% developing incapacitating symptoms or
death over an 8 year follow-up in one large study . In
patients with HCM, age at onset of symptoms, gender, the presence of
obstruction, and genetic mutations impact progression of disease and expected
outcomes  Patients with familial hypertrophic
cardiomyopathy caused by a Phe110Ile missense mutation in the cardiac troponin
T gene have variable cardiac morphologies and a favorable prognosis .
Nonetheless, in patients specifically referred for evaluation of HCM, heart
failure symptoms and outflow tract gradients are common, particularly when
exercise testing is used in the diagnostic assessment .
In patients with HCM, atrial fibrillation (AF) is a common
arrhythmia. A few studies have sought to understand the incidence of AF in
patients with HCM. In a case-control study of 104 HCM patients, AF was present
in approximately 5 percent of patients at the time of diagnosis of HCM and
developed in an additional 10 percent during the subsequent five years of
follow-up . A second study of 480 consecutive HCM
patients, AF occurred in 22 percent over 9 years of follow-up .
In both patient populations the AF subtype was more likely paroxysmal likely
reflecting closer follow-up and the incidence is significantly higher than that
projected from similar age-based general populations. Forty two percent of HCM patients with paroxysmal AF
at presentation progress to chronic AF. In one study, the average progression
time from paroxysmal to chronic AF was 5 years. Occurrence of AF increased
progressively with age and was predominant in patients >60 years of age.
Strong predictors of AF in HCM included age, functional class, left atrial
It is not surprising
that AF is much more common in patients with HCM. These patients have various
degrees of left ventricular hypertrophy and diastolic dysfunction, left atrial
enlargement, and atrial fibrosis [26, 27].
An interesting observation was the atrial fibrosis present in HCM is often out
of proportion to the degree of heart failure present and is similar in extent
to that observed non-HCM patients with advanced heart failure .
An area that requires further study is if atrial myofibril disarray is due to
the ventricular disease only and if it is this atrial myofibril disarray that places
patients at increased risk of AF. Similarly, little is known regarding the
myocardial anatomic structure of the pulmonary vein ostia in HCM patients.
Investigation into the genetic risk of an atrial myopathy and sarcomeric
protein mutations in the atrium may help identify patients at early risk of
An interesting finding is
that dynamic outflow obstruction in HCM does not predict AF .
These data that suggest that patients likely need an atrial predisposition
coupled with the ventricular cardiomyopathy to develop early atrial
The occurrence of AF
represents an important clinical turning point in a HCM patient and has
significant impact on quality of life and mortality with both short and long
term consequences. In a case series of 52 patients with HCM and new onset AF,
the acute onset of AF was associated with worsening of symptoms in 89% of patients
and 93% of patients reverted to their original symptom class after either
rhythm restoration or rate control .
The impact of AF has been well studied in
a large community based HCM study involving 480 patients that were followed up
for 9.1 years . AF developed in 107 patients during
this period. AF onset was associated
with new or worsening clinical manifestations in 84% of the 107 patients.
Clinical manifestations included dyspnea, chest pain, and functional
deterioration in a majority of patients as well as severe symptoms of heart
failure, pulmonary edema, impaired consciousness and syncope in others. In
this study, 74 patients died of HCM-related causes, including 38 (35%) among
the 107 AF patients (sudden death in 13, heart failure–related death in 17, and
stroke-related death in 8). AF was associated with markedly increased risk for
HCM-related death (3% versus 1%, p=0.001) when compared to patients in SR and
was explained by an excess stroke- and heart failure–related mortality (p=0.001).
There was increased incidence of Ischemic strokes among AF patients than among
those in sinus rhythm (21% versus 2.6%, OR 17.7), causing death in 8 patients
and permanent disability in 11. Also patients developing AF before 50 yrs of
age were at greater risk of strokes. Similar increase in stroke risk was also
noted in HCM patients with AF .
Similar findings were
noted in an epidemiological study involving 744 consecutively enrolled and
largely unselected patients across 3 centers followed up for 8 years . HCM-related death occurred in 86 patients (12%, sudden and
unexpected in 51% of these patients), progressive heart failure (36%), and
HCM-related stroke associated with AF (13%) . Data from
these studies highlight the profound impact of AF in these setting of HCM as it
relates to both morbidity and mortality. Although unknown, these findings
suggest that efforts to maintain sinus rhythm may improve outcomes by favorably
impacting disease related morbidity and mortality.
Therapeutic options in HCM patients with AF are similar to those for
patients without HCM. However, due to the association between AF and
progressive HF symptoms, mortality, and stroke, an aggressive approach to the
maintenance of sinus rhythm is often preferred .
There exists a paucity of
data to guide antiarrhythmic therapy in patients with HCM (Table
1). There are no systematic randomized trials to compare the efficacy and
safety of these medications and the information available is largely gleemed
from observational studies of a single drug.
Table 1: Summary of antiarrhythmic medication efficacy and utility in patients with hypertrophic cardiomyopathy
Due to often
significant left ventricular hypertrophy and the potential for proarrhythmia, class
III antiarrhythmic medications are often used. Of these agents, amiodarone is
effective and often used despite a relatively young population. In a case series of 52 consecutive patients with HCM
, 46 developed AF and sinus rhythm was restored in 29
patients (63%) with amiodarone. Of these patients, sinus rhythm was
maintained in 22 of 29 patients during a 5.5 year follow up period. Over this
follow-up period, patients who were treated with amiodarone had fewer
alterations in drug therapy, less embolic episodes, and required less
cardioversions. In another small study with 53 patients with HCM, amiodarone
successfully treated paroxysmal AF/supraventricular tachycardia in 8/9 patients
without provocation of ventricular arrhythmias over a 27 month follow-up period
. In this study, Amiodarone was
discontinued in 3 patients secondary to side effects, but was restarted later
at a lower dose and was well tolerated . However
extrapolation of known side effects of amiodarone that are dose and duration
dependent from other AF populations makes use of this medication long term in the young
HCM patients concerning.
Sotalol may also be helpful in
preventing AF in HCM patients. In a small study of 30 patients, sotalol eliminated supraventricular arrhythmias in 6
of 7 patients and suppressed ventricular arrhythmias in 7 of 13 patients. As
important, 25 patients had better exercise tolerance on sotalol than on
placebo. At a 6 month follow-up period the antiarrhythmic medication remained
effective. In one patient, sotalol induced bronchospasm and had to be
Disopyramide is a class Ia
antiarrhythmic medication that is negatively inotropic. Disopyramide was first
used for patients with obstructive HCM in 1982 largely due to its’ effects on
inotropy. Disopyramide has been shown to provide symptomatic benefit (at 300
mg to 600 mg per day with a dose-response effect) by reducing systolic anterior
motion of the mitral valve, outflow obstruction, and mitral regurgitant volume
[33-36]. Disopyramide has been
recommended to be used in conjunction with a low dose beta blocker as it may be
potentially pro-arrhythmic by accelerating AV nodal conduction and increasing
the ventricular rate in AF. However, disopyramide use in a large multi center
trial of 188 patients with obstructive HCM , 66% of the
patients had a 50% reduction in outflow gradient with amelioration of symptoms
that was maintained over 3 years and did not increase the risk of sudden
cardiac death. However, anticholinergic side effects with disopyramide were common
in this study and consisted of constipation (11%), xerostomia (32%), and urinary
delay/retention (23%). Unfortunately, in non-HCM populations the long-term
maintenance of sinus rhythm with disopyramide is poor ; a finding that is likely worse in patients with HCM with coexistent diastolic dysfunction.
New class III antiarrhythmics such as dofetilide and
dronedarone may also have utility in the treatment of AF in HCM patients,
although their clinical efficacy and safety in this population is not known.
Due to the significant limitations of current antiarrhythmic medications in
patients with HCM, coupled with the consequences of atrial tachyarrhythmias in
HCM, there exists a significant need to define new pharmacologic and
Percutaneous Catheter AF ablation
Catheter ablation with pulmonary vein isolation to
treat AF is being performed with increasing frequency and safety. The
technique has emerged as a first-line therapy in medically-refractive AF  and in one trial was an effective initial treatment
compared to medication . In a recent comprehensive
systemic review of 63 studies that examined both ablation and antiarrhythmic
medications for treatment of AF, the single-procedure success rate
of ablation off all antiarrhythmic therapies was 57% and for
multiple procedures the success rate increased to 71%. In comparison, the
success rate for antiarrhythmic therapies at 1 year was 52%. Of
interest, major complications with catheter ablation occurred in
4.9% of patients compared to a rate of 30% of adverse, but less severe, events
that occurred with drug therapy . The primary
objectives of catheter ablation are to eliminated triggers of AF and modify the
underlying substrate that is responsible for arrhythmia maintenance. Often the
procedure requires extensive ablation in the left atrium particularly in those
with extensive substrate or chronic AF.
Catheter ablation for treatment of AF in patients
with HCM has been reported from multiple centers. The procedural success rates
vary greatly from the different centers from 45-79% [42-46]. The variance in reported
outcomes from these multiple centers likely is due to patient characteristics,
inclusion of patients that had prior ablations, technique approach, and the
follow-up duration. In aggregate, there appears to be additive benefit in a
more aggressive ablative strategy in those with more advanced disease (Figure 2). Unfortunately with broad variance in ablation
strategy, the optimal approach still needs to be defined. We advocate a
stepwise approach with more aggressive linear ablation in those with chronic
disease, severe left atrial enlargement, or presentation with prior ablative
attempts. In understanding the importance of aggressive rhythm control
attempts, in our study , one of the most prominent
findings was the significant improvement in quality of life that was sustained
over the follow-up period after catheter ablation. This finding reflects not
only the procedure as a whole, but the highly symptomatic state of HCM patients
Given the variable results with catheter ablation
we previously tried to understand if echocardiography characteristics and/or
progression of diastolic disease helped determine outcomes. The presence of
diastolic function and severe left atrial enlargement were associated with worse
outcomes. As important, in those patients with advanced diastolic disease and
chronic AF the procedural approach impacted outcomes. This finding is reflective
of the significant atrial arrhythmia substrate with HCM. If patients had
severe left atrial enlargement, advanced diastolic dysfunction, or chronic AF
additional linear ablation was required to obtain favorable outcomes as well as
multiple ablative attempts (Figure 3). Recently atrial
strain has emerged as an intriguing technique to evaluate atrial function.
Strain may be additive in understanding atrial myopathy and assist in atrial
ablation approach . Most of these HCM patients will require more aggressive
ablation approaches as left atrial enlargement and distolic dysfunction are common. For AF ablation in general,an area that requires study is the long-term effects of aggressive ablation on atrial transport function. In patients highly dependent
on the atrial contraction component of ventricular filling, loss of transport may impact quality of
life and disease-related morbidity significantly. As we do not understand the long-term consequence of
aggressive ablation, a stepwise approach may be preferable to minimize extent
of ablation if possible especially in young patients with HCM.
Figure 3: A. Parasternal long axis echocardiogram image of a young patient (age 24) with hypertrophic cardiomyopathy demonstrating severe asymmetric thickness of the septum and left atrial enlargement.
B. Four chamber long axis echocardiogram image of the patient shown in A.
Another area that requires further study is the
underlying atrial anatomy in patients with HCM and if this contributes to
outcomes. Unfortunately, most of the pathologic data revolves around the
ventricular cardiomyopathy. Understanding the anatomy further will help in
choice of ablation tools, duration of energy delivery, endpoints sought, and
AF ablation and Maze procedure
There are less data available
regarding surgical based antiarrhythmic procedures in HCM patients. It is unclear if surgical myectomy will favorably
impact long-term risk of AF. The impact of the surgical approach, if apparent,
will likely require long-term investigation as the presence or severity of an
outflow tract gradient does not appear to be associated with an increased
incidence of AF . In one small case series of septal
alcholol ablation, 3 patients had improvement of AF burden after the procedure
The surgical Maze procedure,
similar to catheter ablation, provides an effective nonpharmacologic approach.
In a case series of 10 patients that underwent a combination Maze III procedure
and myectomy, 80% were in sinus rhythm at a mean of 15 months .
Complications in the relatively higher risk cohort were higher than with
catheter ablation in that two developed complete heart block requiring a
pacemaker and one died 3 months later due to ventricular fibrillation.
There are no case series to
understand the efficacy of a surgical minimally invasive Maze procedure in
patients with HCM. This procedure is a potentially attractive option as the
left atrial appendage can be removed. Likely the ablation approach, whether
with cryothermal or radiofrequncy energy sources, will need to be extensive,
similar to the catheter-based approaches, in order to treat all the arrhythmia
nondihydropyridine calcium channel blockers or both are usually used to treat
the ventricular rate. Digoxin can increase inotropy which may exacerbate heart
symptoms in patients with HCM that have preserved systolic function. In
patients that have refractory AF with rapid ventricular rates, atrioventricular
node ablation and permanent pacing is an alternative.
patients with HCM have various levels of diastolic dysfunction that progresses
in severity over time. The organized atrial contraction is often an important
contributor to left ventricular filling in patients with diastolic dysfunction
. Loss of the atrial component of filling despite
control of the ventricular rate may still significantly impact quality of life
and prompt the need to reconsider aggressive rhythm control strategies as the primary approach to improve outcomes.
occur up to eight times more frequently with AF in HCM than in sinus rhythm
. The risk of stroke increases with age; in the Framingham Study, the
annual risk of stroke attributable to AF increased from 1.5% in participants
aged 50 to 59 years to 23.5% for those aged 80 to 89 years. In HCM, the risk of
AF is higher with an incidence of 2%/yr and prevalence of 22%. In another large
community based cohort of 900 patients with HCM, the overall incidence of
stroke and peripheral arterial embolic events was 0.8%/year and 1.9% for patients >60 years. As expected, the
cumulative incidence of these events was significantly higher in non-anticoagulated patients as compared with patients on warfarin (31% vs. 18%; p < 0.05) .
HCM patients who develop AF should be considered to be at moderate to high risk
and should be anticoagulated with warfarin. Further study is required to
understand if aggressive measures to keep patients in SR decrease stroke risk
in the setting of anticoagulation.
advances and successes of nonpharmacologic approaches to restore sinus rhythm,
there arises the question of discontinuing warfarin anticoagulation. The
recent Heart Rhythm Society guidelines 
conclude that the long-term use of warfarin anticoagulation should be based
upon the underlying patient risk. Patients with HCM are now low risk, a
profile that would suggest they can be effectively and safely treated with
aspirin only. Given, their baseline moderate risk status, warfarin should be
continued until data are available to suggest otherwise or the risk of bleed is
greater than the risk of stroke based upon the presented epidemiologic studies.
Patients with HCM are
at high risk of developing AF particularly in the setting of advanced diastolic
dysfunction and left atrial enlargement. AF is a marker of increased mortality
and morbidity and results in a significant reduction in quality of life.
Antiarrhythmic medications improve symptoms and reduce AF recurrence, but few
are safe and there exists little data to guide their long-term use in HCM.
Non-pharmacologic approaches have emerged and have equal or greater efficacy
than pharmacologic approaches. Although these approaches are promising, the
long-term impact on atrial function needs to be carefully studied as it may
impact quality of life in patients that age in the setting of a progressive
diastolic disease disorder. Nonetheless, with the significant impact of AF in
HCM, rhythm control strategies that are often aggresive with associated risk are required. The understanding of rhythm
control strategies in HCM, an often rapidly progressive diastolic dysfunction
disorder, may provide insight in how to treat the much more prevalent AF
patient with hypertensive cardiomyopathy.
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