Atrial fibrillation in hypertrophic cardiomyopathy: a turning point towards increased morbidity and mortality

Atrial fibrillation in hypertrophic cardiomyopathy A turning point towards increased morbidity and mortality Accepted Manuscript Atrial fibrillation in hypertrophic cardiomyopathy A turning point towa[.]

Atrial fibrillation in hypertrophic cardiomyopathy: A turning point towards increased

morbidity and mortality

Thomas Zegkos, MD, Georgios K Efthimiadis, MD, Despoina G Parcharidou, MD,

Thomas D Gossios, MD, Georgios Giannakoulas, MD, Dimitris Ntelios, MD, Antonis

Ziakas, MD, Stelios Paraskevaidis, MD, Haralambos I Karvounis, MD.

DOI: 10.1016/j.hjc.2017.01.027

Reference: HJC 139

To appear in: Hellenic Journal of Cardiology

Received Date: 18 October 2016

Revised Date: 12 January 2017

Accepted Date: 20 January 2017

Please cite this article as: Zegkos T, Efthimiadis GK, Parcharidou DG, Gossios TD, Giannakoulas G, Ntelios D, Ziakas A, Paraskevaidis S, Karvounis HI, Atrial fibrillation in hypertrophic cardiomyopathy:

A turning point towards increased morbidity and mortality, Hellenic Journal of Cardiology (2017), doi:

10.1016/j.hjc.2017.01.027.

This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Authors: Thomas Zegkos MD, Georgios K Efthimiadis MD, Despoina G

Parcharidou MD, Thomas D Gossios MD, Georgios Giannakoulas MD, Dimitris Ntelios MD, Antonis Ziakas MD, Stelios Paraskevaidis MD, Haralambos I Karvounis

MD

Affiliation: 1st Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation

Running title: Atrial fibrillation in hypertrophic cardiomyopathy

Address for correspondence:

Thomas Zegkos

AHEPA University Hospital, Aristotle University of Thessaloniki

1 Stilponos Kyriakidi Street 54636,

Background: Atrial fibrillation (AF) is the most common arrhythmic event in

patients with hypertrophic cardiomyopathy (HCM) The aim of this study was to identify the clinical and the prognostic impact of the arrhythmia on a large cohort of patients with HCM

Methods: The echocardiographic and clinical correlates, the predictors of AF and

thromboembolic stroke and the prognostic significance of the arrhythmia were evaluated in 509 patients with an established diagnosis of HCM

Results: A total of 119 (23.4%) were diagnosed with AF at index evaluation visit AF

patients had higher prevalence of stroke and worse functional impairment Left atrial diameter (LA size) was a common independent predictor of the arrhythmia (OR: 2.2, 95% CI 1.6-3.3) and thromboembolic stroke (OR: 1.6, 95% CI 1.01-2.40) AF was an important risk factor for overall (HR=3.4, 95% CI: 1.7-6.5), HCM-related (HR=3.9, 95% CI: 1.8-8.2) and heart failure-related mortality (HR=6.0, 95% CI: 2.0-17.9), even after adjusting for the significant clinical and demographic risk factors However, it did not affect the risk for sudden death

Conclusions: LA size was a common predictor of the arrhythmia and

thromboembolic stroke AF patients, regardless of the type of the arrhythmia, displayed significantly higher mortality rates

Keywords: hypertrophic cardiomyopathy; atrial fibrillation; left atrium; mortality;

morbidity

Abbreviations: AF: atrial fibrillation; CMR: cardiac magnetic resonance; CPEx:

cardiopulmonary exercise testing; EF: ejection fraction; HCM: hypertrophic cardiomyopathy; LA size: left atrial diastolic diameter; LGE: late gadolinium enhancement; LV: left ventricle; LVEDD: left ventricular end-diastolic diameter; NYHA: New York Heart Association; SR: sinus rhythm

Methods

Study Population

All the patients with an established diagnosis of HCM that were evaluated in the Cardiomyopathy Center of AHEPA University Hospital from 1995 until 2014 were assessed retrospectively according to the presence of AF at index evaluation visit Clinical, imaging and functional parameters were examined The retrospective, purely observational type of this study did not necessarily require the acquisition of informed consents or ethics committee approval

Definitions

Atrial Fibrillation

AF was diagnosed on the basis of an electrocardiographic or Holter monitor recording

as it was previously described [16] or by an established history of the arrhythmia AF was considered paroxysmal when it was self terminated or successfully converted to sinus rhythm (SR) within 7 days Any other type of the arrhythmia was considered non paroxysmal

Study Outcomes

Overall mortality was defined as death rate by any cause during the follow up period HCM-related mortality consisted of deaths directly attributed to the primary disease such as sudden, stroke-related and heart failure-related deaths Sudden cardiac death was defined as a sudden and unexpected collapse in patients, in the absence of symptoms, who had previously experienced a relatively stable clinical course Heart failure related-mortality was defined as death rate in the context of refractory or

progressive heart failure over one year before death [5]

Echocardiography

The echocardiographic measurements were obtained with a Sigma 1 ratio (Kontron

AG, Ausburg, Germany) instrument until 2003, and a GE Vivid 7 ultrasound

Cardiac Magnetic Resonance

Cardiac magnetic resonance (CMR) was performed with a clinical 1.5-T imager (Magnetom Vision; Siemens, Erlangen, Germany) Late gadolinium enhancement (LGE) images were obtained 10-15 min after intravenous administration of 0.2 mmol·kg-1 gadolinium-DTPA, using an inversion recovery turbo Fast Low Angle Shot (FLASH) sequence with 6 mm slice thickness at the same position as the long- and short-axis cines in end diastole [20]

Cardiopulmonary Exercise Testing

Exercise capacity was assessed by peak oxygen consumption that was measured by cardiopulmonary exercise testing (CPEx) as previously described [21] Exercise was performed in a Schiller Cardiovit CS 200 (Schiller America, Doral, FL, USA) Ergo-

Statistical Analysis

Continuous variables with normal distribution were reported as mean±SD and were compared using Student t test Categorical variables were expressed as frequencies and percentages and were compared using chi-square (x2) test or Fisher’s exact test for small samples relatively Odds ratios (OR) were measured with univariate and multivariate binary logistic regression models Τhe statistical significant factors were included in multivariate analysis Receiver operator characteristic (ROC) analysis was performed in order to obtain the optimal cutoff value of LA size for predicting

AF and thromboembolic stroke Differences in survival in patients with and without

AF were assessed with Kaplan-Meier’s analyses, and p values were derived by rank testing Hazard ratios (HR) were originated by use of univariate and multivariate Cox proportional-hazard regression models The statistical significant clinical and demographic risk factors were included in the multivariate hazard models P value

log-<0.05 was considered significant Statistical analysis was performed with SPSS for windows version 22 (IBM corp, Armonk, New York)

Results

Baseline Characteristics

A total of 509 patients with diagnosed HCM were analyzed retrospectively Mean age

at the time of first evaluation was 51.0±15.9 years and 341 (67%) patients were male Maximal wall thickness was 2.0±0.5cm, LA size 4.2±0.7cm and mean EF 71.2±12.9% Resting or provoked LVOT obstruction was present in 129 (25.3%) of patients A total of 70 (13.8%) patients had positive family history for sudden death and 52 (10.2%) had apical hypertrophy New York Heart Association (NYHA) class III or IV characterized 73 (14.3%) patients B-blockade therapy was being administrated in 302 (59.2%) patients The baseline characteristics of the population are displayed in Table 1

AF prevalence and its relation with clinical, imaging, and functional Parameters

A total of 119 (23.3%) patients were diagnosed with AF at baseline Mean age of patients with AF was 51.6±15.9 and 53.8% were male Paroxysmal AF was diagnosed

in 79 (15.5%) patients (mean age 49.0±12.5 years, 49.4% male) and non paroxysmal

in 40 (7.8%) HCM patients (mean age 51.4±16.1 years, 62.5% male)

Clinical and imaging characteristics as well as laboratory values of patients according

to the presence of AF are displayed in Table 1 AF was most common in women Also

AF patients had more often a confirmed history of stroke (13.4% vs 6.7%, p=0.019) Unexplained syncope was more frequently observed in patients with AF, however, the emergence of nonsustained ventricular tachycardia as well as a positive family history for sudden death displayed only borderline association with the arrhythmia AF

Of note, CPEx was performed in individuals with paroxysmal AF when they were in

SR

On echocardiography, LA size, LVEDD and E/E’ of the interventricular septum and

of the lateral wall were significant higher in patients with AF, but maximal wall thickness, and EF did not differ substantially There seemed to be a trend towards an association between obstructive HCM and the arrhythmia The severity of mitral regurgitation also correlated with the absence of normal rhythm CMR that was performed in 129 patients demonstrated that AF at baseline was not associated with the presence of LGE

Patients with non paroxysmal type of the arrhythmia had significantly larger LA, higher maximal wall thickness and worse functional capacity (Table 2)

AF and thromboembolic stroke predictors

Thromboembolic stroke was predicted only by AF and LA size in univariate analysis (Table 4) When both of the above factors were included in a multivariable model, LA size maintained its significance (OR: 1.06, 95% CI: 1.01-2.44; p=0.043) (Table 4) Moreover, a ROC curve of LA size as a predictor for stroke indicated an AUC 0.6 (95% CI 0.52-0.70) (figure 1B) The optimal cutoff value was once again 4.2 cm with sensitivity 71% (67%-75%) and specificity 49% (45%-53%)

Survival analysis

In a mean follow up of 9±5 years an overall of 36 (7.1%) patients died Eighteen patients had AF and 18 were in SR at index evaluation Significantly more patients with AF suffered HCM-related (12.6% vs 3.3%, p<0.001) and heart failure-related death (7.6% vs 1.3%, p=0.001) than patients in SR Prevalence of sudden cardiac death did not differ significantly between the two groups (Table 5)

Among the 18 patients with AF that died, 13 had paroxysmal and 5 non paroxysmal arrhythmia at index evaluation visit The type of the arrhythmia did not affect the survival

Discussion

HCM is a genetically heterogeneous disorder, characterized by various clinical presentations and outcomes It is reasonable to assume, that this genetic heterogeneity may also be linked with differences in the frequency or the clinical impact of AF Therefore, regional studies concerning this subject are important because they may reveal inconsistencies that may directly reflect the diverse genetic substrate of the disease

In this regard, the impact of AF in a large northern Greek population with HCM has never been studied before The prevalence of AF, paroxysmal or non paroxysmal, in

to the deterioration of symptoms and constitutes a turning point towards increased morbidity In line, patients with AF of our cohort had higher prevalence of thromboembolic stroke and worse functional status as reflected by the NYHA class Moreover, the exercise capacity of 126 patients who underwent CPEx was worse when AF of any type was present in agreement with our previous study which revealed AF as an independent predictor for exercise intolerance in HCM [23] It is interesting that although patients with paroxysmal AF underwent the CPEx when they were in SR, their functional capacity was reduced when compared to those without any history of AF This finding confirms that regardless of the underlying rhythm, the history of paroxysmal AF is related with more advanced disease [24]

Our study failed to find an association between the presence of LGE in the LV myocardium and AF incidence although myocardial scarring may lead to the diastolic impairment of the LV, which is, as aforementioned, closely linked to the development

of a large HCM population also reported a similar percentage at index evaluation visit, however, this did not have an influence on the mortality of AF patients [31] This can be explained with the fact that the much broader use of anticoagulants begun the last decade

The severity of mitral regurgitation was significantly associated with the arrhythmia and there seemed to be a trend towards the association between obstructive HCM and

AF Generally, the above result seems reasonable due to the close relationship of the above two factors with LA enlargement [30, 32] However, the association of the LV outflow obstruction with AF has not been unequivocally established, as data from

AF appears to be a pivotal modifier of the mortality in patients with HCM, although there are studies that demonstrate that the arrhythmia’s effect is actually minor.[1, 13, 34] Our study confirms that AF conferred an increased risk for overall, HCM-related and heart failure-related mortality Although some reports suggest an association between AF and lethal ventricular arrhythmias [35, 36], our study’s results do not support the arrhythmia as a risk factor for sudden death

The type of AF at index evaluation visit was not found to affect survival However, it

is reasonable to assume that HCM patients with exclusively paroxysmal arrhythmia display lower cardiac mortality and lower incidence of heart failure compared to those progressing to non paroxysmal type, due to the persistently elevated ventricular rate

of the latter, in line with non-HCM population [37, 38] In our study, the proportion of patients with paroxysmal that progressed into non paroxysmal AF after the index evaluation was not taken into account This fact, along with the subsequent low number of observed events in the latter group, may explain the above controversy

Study limitations

The retrospective design of this study is the most important and unavoidable limitation, inherent to HCM as the low incidence of the disease and the even lower incidence of AF in these patients, renders prospective studies in large patient populations unfeasible Also, patients were classified according to the presence of the