Practical and summarized recommendations for the clinical management of atrial fibrillation
and sudden death risk stratification of patients with hypertrophic cardiomyopathy
ALEJANDRO BRAVO, MARCELO COLL, FRANCISCO A. FEMENIA,
HÉCTOR S. MANZOLILLO, ANDRÉS MARTELLOTTO, GERARDO A. MORENO,
ROLANDO E. PANTICH, ARIEL E. SZYSZKO, MARIANA VALENTINO,
DIEGO VELASCO, ALEJANDRO A. VENTURA.
Comité de Arritmias y Electrofisiología. Federación Argentina de Cardiología (FAC)
(3300) Posadas, Misiones, Argentina. E-mail
Recibido 09-ABR-2018 – ACEPTADO el 02-MAYO-2018.
There are no conflicts of interest to disclose.
Hypertrophic Cardiomyopathy (HCM) is defined by the presence of increased thickness of the left ventricle wall (≥15 mm) that cannot be explained solely by abnormal loading conditions. The most frequent and known etiology of HCM is autosomal dominant genetic, caused by mutation of genes that encode for sarcomere proteins. Estimated prevalence is around 1 out of 500 people in the general population. Throughout the years, applying clinical research, we have learned that these patients have an increased risk of both atrial and ventricular arrhythmias, and they contribute greatly to the patient prognosis, morbidity and mortality.
The Arrhythmias and Electrophysiology Committee of the Argentine Federation of Cardiology, decided to review the current literature in order to provide a summary and practical information for the proper clinical management of these patients, mainly as regards the clinical management of Atrial Fibrillation (AF) and the Stratification of Sudden Cardiac Death (SCD) Risk, in order to try to help clinical cardiologists to select the best management strategy in each individual patient.
These recommendations by the Committee on Arrhythmias and Electrophysiology of the Federación Argentina de Cardiología (FAC) on the clinical management of Atrial Fibrillation (AF) and Risk Stratification of Sudden Cardiac Death (SCD) in patients with Hypertrophic Cardiomyopathy (HCM) have as their main goal to present current relevant evidence on these particular issues, to help clinical cardiologists to select the best strategy to manage each patient individually. Also, we attempted to simplify the recommendations from international guidelines on management of HCM, updating the evidence that would provide information to follow current therapeutic managements.
When we discuss Hypertrophic Cardiomyopathy, we mean a cardiomyopathy that is defined by the presence of greater thickness of the left ventricular wall, which cannot be explained solely by anomalous load conditions . This definition is applied to children and adults, and makes no assumptions on the etiology and myocardial condition. The most frequent HCM and the one about which we have more information, is an autosomal dominant genetic disorder caused by the mutation in the genes that encode sarcomere proteins. A prevalence of 1 in 500 people in the general population is estimated . There are multiple genetic polymorphisms that are associated to this pathology, and that generate a marked heterogeneity in its clinical presentation. The main anatomopathological features are cardiac muscle hypertrophy (≥15 mm with no hemodynamic cause to justify it) and myocardial tissue disarray.
With the passing years, and as a result of clinical investigation, we have learned that these patients present a greater risk of arrhythmias, both atrial and ventricular, and that they contribute to a great extent to the prognosis, morbidity and mortality of the patient . The Committee on Arrhythmias and Electrophysiology of FAC decided to review current literature with the goal of contributing practical and summarized information for an appropriate clinical management of these patients.
More than 3 decades ago, a system of evidence was introduced, that works as a model for the critical assessment of literature, assigning a degree to each recommendation (I, II or III), besides pointing out the strength of evidence on which the recommendation is based (A, B, C). The recommendations for the use or not of a procedure or treatment in particular are based on the risk-cost/benefit ratio. The level or strength of evidence of recommendation emerges from the methodological strength of studies for the validation, consistency and generalization of results.
Degree of recommendation of International Guidelines
Grade I: Evidence and/or general agreement about a given procedure/treatment is beneficial, useful and effective.
Grade II: Conflictive evidence and/or divergence of opinions about the usefulness/efficacy of the procedure/treatment.
Grade IIa: The weight of evidence/opinion is in favor of usefulness/efficacy.
Grade IIb: The usefulness/efficacy is less settled for evidence/opinion.
Grade III: General evidence or agreement about the treatment not being useful/effective, and even being harmful in some cases.
Level of evidence
Level A: Data from multiple randomized clinical trials or meta-analysis.
Level B: Data from a single randomized clinical trial or from non-randomized observational studies.
Level C: Consensus of opinion by experts and/or small studies.
Although from the beginning HCM was always directly related to ventricular arrhythmias and the risk of sudden cardiac death, today we can state that in fact, Atrial Fibrillation is the most frequent arrhythmia in these patients. The current European Guideline of clinical practice on the diagnosis and management of Hypertrophic Cardiomyopathy , presents us with statistical information on the incidence (3.1% yearly) and prevalence (22.5% yearly) of this arrhythmia, which expresses its clear significance, as it entails an incidence (3.8% yearly) and prevalence (27.1% yearly) of stroke; clearly increased in comparison to patients with AF but no HCM.
It is relevant to bear this arrhythmia in mind always in each of the patients with diagnosis of HCM, as it will be responsible to a large extent, for the quality of life and the significant risk of stroke.
For this reason, we highlight in a practical and brief way, certain recommendations for clinical management.
A proper control of cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia, sedentarism, obesity, obstructive sleep apnea) is advisable to be able to decrease the incidence of AF, as well as its recurrence, both in the general population and in patients with HCM [4,5].
In patients with HCM that require antihypertensive treatment, it is advisable to do it with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), as there are numerous meta-analyses supporting this. Recently, it was observed that in the particular group of patients with HCM, the risk of developing AF would decrease when treated with renin-angiotensin-aldosterone system inhibitors .
Consider always the 2-dimensional echocardiographic atrial diameter (>45 mm), the duration of P wave (>140 ms) and the pressure gradient in the left ventricular outflow tract (obstructive gradient), as the main predictors for the development of AF in HCM .
AF screening should be made in all patients with HCM and left atrium with anteroposterior diameter ≥45 mm, by 48 h Holter every 6 months  (class IIa, Level of evidence C).
The high density of supraventricular extrasystole (SVES) (≥30 SVES/hour) or self-terminating atrial salvos of more than 20 consecutive beats in patients with HCM, showed association with stroke development, independently from AF, and for this reason they should be considered risk predictors in the follow-up of patients .
We should be thorough to detect this arrhythmia, to follow the preventive measures for stroke timely, and to permanently educate patients on heart rhythm self-monitoring.
Unless contraindicated, ALL patients with diagnosis of HCM and AF (in any of its presentations: paroxysmal, persistent, permanent) should be anticoagulated orally (Class I, Level of evidence C); whether with vitamin K antagonists (acencoumarol or warfarin) with INR from 2 to 3, as first-line option or with direct oral anticoagulants (dabigatran, rivaroxaban, apixaban) as second line option when the former are not properly tolerated, could not maintain the anticoagulation range, or a proper monitoring was not possible [1,8] (Class I, Level of evidence B).
Patients with HCM and AF in treatment with direct-acting oral anticoagulation (DOAC) displayed a similar rate of embolic events and hemorrhagiparous complications when compared to patients treated with vitamin K-dependent oral anticoagulation. In general, patients with DOACs expressed a greater satisfaction in follow-up .
The CHADVASc NO score is applicable to patients with AF and HCM. They should be anticoagulated always and for a lifetime, unless contraindicated [1,8] (Class I, Level of evidence C).
The HASBLED score could be used to assess the risk of hemorrhagiparous in patients with HCM that require oral anticoagulation  (Class IIa, Level of evidence B).
It is important to adopt an early and aggressive strategy for rhythm control in patients with paroxysmal or persistent AF to prevent its recurrence, as this arrhythmia will facilitate the appearance of heart failure and stroke.
In patients with acute AF and the presence of hemodynamic failure signs, electrical cardioversion should be applied, with the previous administration of low molecular weight heparin (e.g., enoxaparin 1 mg/kg of weight), followed by oral anticoagulation after the procedure. If there are no signs of hemodynamic decompensation, it is possible to consider pharmacological cardioversion with load and maintenance of IV amiodarone (Class IIa, Level of evidence C).
To perform a scheduled electrical cardioversion, a minimum of 3 weeks of oral anticoagulation is required, in a range (INR 2-3) for drugs as acenocoumarol or warfarin, or 3 weeks of treatment with DOACs (dabigatran, apixaban, rivaroxaban).
To maintain sinus rhythm, the antiarrhythmic drug amiodarone is recommended  (Class IIa, Level of evidence B).
For rhythm control, pulmonary veins ablation is an alternative to be considered in symptomatic patients with recurrent paroxysmal or persistent AF. The rate of success is lower when compared to patients without HCM (maintenance of post-ablation sinus rhythm of 67% during 29 months of follow-up)  (Class IIa, Level of evidence B).
For rhythm control in patients with HCM, an early and aggressive treatment is advisable.
For ventricular rate control, it is advisable to use beta-1 selective blockers (metoprolol, bisoprolol, atenolol) or non-dihydropyridine calcium channel blockers (verapamil or diltiazem) [1,8] (Class I, Level of evidence C).
Using digoxin in patients with left ventricular outflow tract is not advised, and neither is using class IC antiarrhythmics (flecainide or propafenone) due to the risk of prolonging QRS and QT intervals duration, a scenario that predisposes to complex ventricular arrhythmias .
RISK STRATIFICATION OF SUDDEN CARDIAC DEATH When discussing prevention of sudden cardiac death in patients with HCM, both in primary prevention as in secondary prevention, we should consider implementing it by implantable cardioverter defibrillator (ICD), as no other therapeutic option (pharmacological or surgical) has shown to decrease the incidence of SCD.
We should emphasize that ICD implant in these patients is far from being a practice free from unwanted events. It is not just a surgical procedure, with complications proper of an invasive technique (infections, bleeding, catheter displacement or fractures, etc.) but complications may also occur during follow-up, affecting the quality of life of the patient, and may alter left ventricular systolic function in the mid to long term.
In secondary prevention, that is to say in patients that have suffered an SCD event and recovered from it, or in patients in whom ventricular fibrillation or sustained ventricular tachycardia was recorded with hemodynamic decompensation, there are no doubts as to the benefit that ICD implant would provide, as the rate of recurrence of a new SCD or VF/VT episode is 10% per year .
In primary prevention, the risk of SCD varies from 0.5 to 1% per year ; for this reason, it is extremely important to perform a proper risk stratification for sudden cardiac death before indicating ICD implant, and thus achieve the balance between SCD prevention and the possible adverse effects of the therapy.
In the management of patients with HCM, international guidelines propose different strategies when evaluating the risk of these patients, with different levels of evidence to each of the predictors described to this date.
In 2011, the American Heart Association and the American College of Cardiology (AHA/ACC) , recommend in a graded way, the following predictors:
With the presence of any of the following predictors; i.e. history of SCD in first-degree relatives, parietal thickness ≥30 mm, or unexplained syncope, ICD implant is presented as reasonable.
In the absence of the previously mentioned predictors, the following are next in importance: presence of nonsustained ventricular tachycardias (NSVT) in Holter, or abnormal response to blood pressure in ergometer test (hypotension, or NO increase in blood pressure during exercise). With one of these major predictors, and a minor predictor (obstruction gradient in the left ventricular outflow tract, presence of late gadolinium enhancement in cardiac magnetic resonance, presence of apical aneurysm, or the presence of one of the chromosomal mutations described as malignant) suggest that ICD implant could be useful.
In 2014, the European Society of Cardiology (ESC)  proposed using one risk application based on predictors similar to the abovementioned ones, but prioritizing other new predictors that also showed association with SCD in carriers of HCM. In this calculator, the following predictors are included: patient’s age, maximum parietal thickness of the left ventricle, anteroposterior diameter of the left atrium, maximum gradient in left ventricular outflow tract, presence or absence of history of SCD in 1st degree relatives, presence or absence of nonsustained ventricular tachycardia, and the presence or absence of unexplained syncope.
With these parameters, some quantitatively continuous and other binary ones, a complex mathematical estimation of risk in 5 years is made, the result of which poses that with <4% of SCD risk, ICD implant should not be indicated; in patients with 4-6% risk of SCD, the implant “could” be considered; and in patients with >6%, the implant “must” be considered.
Limitations of predictive models
The AHA/ACC predictive model reaches a Positive Predictive Value of 10-20% only (very low); and the ESC model does not include elite sportsmen, patients <16 years, HCM by metabolic or infiltrative diseases, and does not specify whether the left ventricular outflow tract gradient induced by exercise represents a risk predictor, neither clarifies what happens with the patients undergoing septal myomectomy or alcohol septal ablation by symptomatic severe left ventricular outflow tract obstruction.
A central problem of risk predictors for primary prevention are the inconsistencies shown by controlled studies that assessed their association, whether because of the diversity of the population studied, or by the diversity of the definitions used to describe each of these predictors.
These inconsistencies impose practical hindrances at the time of properly stratifying patients in the medical office, in daily practice, not knowing for certain whether it is convenient to use the European application of risk, or the American predictive model to stratify SCD risk.
One of these inconsistencies is the family history of SCD, not always taken into account as a risk predictor for HCM, as there was a marked variability in the definitions used in the different studies evaluating this variable; in some cases, not exceeding the multivariate analysis, and in other there wasn’t even any statistical association . The cutoff point for the age of the relative that suffered SCD to become a risk predictor is also controversial (<30 years, <35 years, <40 years, <50 years?) .
Another inconsistency is syncope as risk predictor of SCD, mainly for the accurate diagnosis of the pathophysiological mechanism that triggers SCD (vasovagal, reflection arrhythmia?). We don’t know either, if a syncope with obstructive HCM or nonobstructive HCM has the same predictive value. Recently, it became evident that history of unexplained syncope, but having occurred >6 months at the time of the consultation, does NOT constitute a risk predictor .
Another inconsistency in HCM is nonsustained ventricular tachycardias (NSVT) with multiple definitions adopted in controlled clinical studies, that showed the association of risk with SCD . It is not clear either if their predictive value is established with 24 h or 48 h Holter, and the electrophysiological characteristics were not taken into account, quite diverse indeed, to learn if they are really risk predictors .
For these reasons, the Committee on Arrhythmias and Electrophysiology of FAC, after thoroughly reviewing and analyzing international guidelines and current evidence, proposes to consider the following risk predictors of SCD, in the order explained in Figure 1, considering first the predictors endorsed by both predictive models; i.e. American and European, that present the highest number of investigation studies to back them up, with a statistically significant association strength for the risk of sudden cardiac death, and next the rest of risk predictors to take into account to define the indication of ICD in primary prevention.
Figure 1. Order proposed to consider SCD risk predictors in patients with HCM
for their stratification and choice of management
Predictors to consider for the sudden cardiac death risk stratification in patients with hypertrophic cardiomyopathy
History of sudden cardiac death in first-degree relatives (parents, siblings, sons and daughters) with ages >40 years.
Unexplained syncope (with no accurate diagnosis of the triggering pathophysiological mechanism) within 6 months before the consultation.
Maximum parietal thickness, as continuous variable; i.e. that is not just a risk predictor if it exceeds 30 mm, but the greater the thickness, the greater the risk.
Nonsustained ventricular tachycardias (≥3 consecutive beats, ≥120 beats per minute) in 24 h or 48 h Holter.
Abnormal response of blood pressure during exercise, with impossibility to increase systolic pressure at least 20 mmHg since rest to maximum exercise, or drop >20 mmHg since the peak of blood pressure.
Age as a risk factor, emphasizing <40 years (greater risk).
Maximum gradient in the left ventricular outflow tract (taking into account always the great dynamic variability of it, according to multiple conditions).
Anteroposterior diameter of the left atrium.
Late gadolinium enhancement ≥25% in cardiac NMR.
“Malignant” genetic mutations: polymorphisms in the beta-myosin heavy chain gene, of protein C binding to tropomyosin, or troponin T.
Presence of apical aneurysm in the left ventricle.
Left ventricular dysfunction.
Increased biomarkers, such as: troponin I and troponin T, brain natriuretic peptide (BNP), high sensitivity C-reactive protein (hsCRP).
Electrophysiological characteristics such as: presence of primary negative T waves (i.e. with normal QRS complexes) , microvolt T-wave alternans in ergometer test , presence of fragmented QRS complexes, QT-interval dispersion , among others.
Cardiopulmonary ergometer test with analysis of ventilation and carbon dioxide (VE/VCO2) slope with cutoff point ≥31, that is associated to a greater incidence of SCD .
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