Abstract
Background
Atrial fibrillation (AF) is a common complication in patients with hypertrophic cardiomyopathy (HCM) and may contribute to high cardiovascular morbidity and mortality. Therefore, it is important to assess parameters associated with AF in HCM patients.
Hypothesis
The aim of the study was to evaluate AF prevalence in patients with HCM and to investigate risk factors for AF.
Methods
Five hundred and forty‐six HCM patients aged below 65 were included into analysis. Clinical and echocardiographic parameters were analyzed.
Results
In 141 patients (25.8%) AF episodes were recorded. The following factors were identified as risk factors for AF in patients with HCM: age ≥ 45 years (OR 2.38, CI 1.40‐4.05, P = 0.001), past history of presyncope or syncope (OR 2.25, CI 1.35‐3.74, P = 0.002), non‐sustained ventricular tachycardia (nsVT) (OR 2.70, CI 1.60‐4.57, P < 0.001), left atrium diameter during first assessment (OR 1.065, CI 1.03‐1.11, P = 0.001), left atrium diameter at the last assessment before AF occurrence (OR 1.10, CI 1.06‐1.14, P < 0.001) and left ventricular ejection fraction at the last assessment before AF occurrence (CI 0.96, CI 0.94‐0.98, P = 0.001).
Conclusions
We confirm that AF is a common complication for patients with HCM. Identification of patients with high risk for AF and implementation of preventive strategies may reduce AF occurrence and its complications.
Keywords: atrial fibrillation, hypertrophic cardiomyopathy, risk factors
1. INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is one of the most common cardiac genetic diseases, with a prevalence of 1:500 in the general adult population.1 Atrial fibrillation (AF) is an arrhythmia often complicating the course of HCM. Patients with HCM have higher risk for AF and it will eventually develop approximately in one out of five of HCM patients.2, 3 This arrhythmia is associated with substantial cardiovascular morbidity and mortality by promoting progressive congestive heart failure and increasing the risk for systemic thromboembolism.2, 3, 4, 5, 6 Early detection of susceptibility to AF is crucial to prevent complications. A number of clinical and echocardiographic markers have been identified as risk factors for AF. The purpose of this study was to evaluate the incidence of AF and identify clinical and echocardiographic parameters associated with risk for AF in patients with HCM.
2. METHODS
Patients with HCM under clinical care of The Institute of Cardiology in Warsaw, evaluated in 2016 during their scheduled yearly visit were included into analysis. In order to minimize influence of parameters associated with presence of AF in general population patients younger than 65 were included into analysis. Retrospective analysis was undertaken for 546 HCM patients.
Patients' clinical and demographic parameters including non‐sustained ventricular tachycardia (nsVT) on ECG Holter monitoring, family history of HCM or sudden cardiac death (SCD), past history of presyncope or syncope were collected.
Furthermore, the following echocardiographic parameters were assessed at initial and last follow‐up visit before AF development: left atrium (LA) diameter, left ventricular ejection fraction (LVEF), left ventricle wall thickness (LVWT), maximum left ventricular outflow tract (LVOT) gradient and the presence of systolic anterior motion of the anterior mitral valve leaflet (SAM). The examinations were performed using standard method by a cardiologist certified in echocardiographic evaluation.
Family history of sudden cardiac death was defined as unexplained death in at least a second degree relative below 40 years of age or, in older relatives—death of a person with diagnosed HCM if other cause of death was not evident. Hypertension was defined as blood pressure over 140/90 mmHg or patient treated for hypertension or diagnosed metabolic syndrome, according to International Diabetes Federation criteria.7 Body mass index (BMI), blood pressure, waist circumference (and if available glucose, HDL‐cholesterol, and triglycerides level) were collected at each visit. Values from the last visit preceding AF or, in case of non‐AF patients, from the last visit, were used for calculations.
AF evaluation: All patients had sinus rhythm during initial evaluation. During follow‐up all 12‐lead ECGs, 24‐hour ECG Holter recordings and ICD/DDD memory readings were reviewed for episodes of AF. The diagnosis of AF was based on at least one episode of AF registered in ECG recording, during 24‐hour ambulatory Holter ECG monitoring, ICD/DDD memory review or established history of AF in medical records. If AF episodes were detected, we recorded patient's age at the time of occurrence and all other relevant clinical data available during last assessment on sinus rhythm. Based on the occurrence of AF patients were assigned into one of two groups: the AF group and the non‐AF group.
The study was approved by the Institutional Ethics Committee, with written informed consent obtained from all patients agreeing to the use of their medical information for research purposes.
2.1. Statistical analyses
Continuous variables were expressed as means ± SD, and categorical variables were presented as frequencies (n) and percentages (%). The Mann‐Whitney test was applied to continuous variables. Differences in non‐continuous variables were compared using the χ2 test. P values less than 0.05 were considered statistically significant. Parameters were assessed with univariate and multivariate logistic regression analysis. Multivariate analyses were conducted using a stepwise forward regression model, in which each variable with a P value < 0.05 in the univariate analysis was entered into the model.
3. RESULTS
3.1. Patient characteristics
The study cohort comprised 546 HCM patients (373 men), aged 46.1 ± 13.7 years. In 141 (25.8%) patients AF episodes were noted.
Overall, 381 (69.8%) patients had a positive family history of HCM and 178 (32.6%) patients—a family history of sudden cardiac death (SCD). The mean LV septal thickness was 21.3 ± 6.2 mm, and LA diameter 45.1 ± 8.6 mm.
The baseline characteristics of the studied population are presented in Table 1. Patients with at least one episode of AF were older, had more common history of presyncope/syncope, occurrence of nsVT, were obese or overweight, had hypertension and metabolic syndrome. Echocardiographic findings showed that AF group patients had initially a more dilated left atrium with LA long axis parasternal dimension of 44 ± 8.1 mm compared with 37.5 ± 7 mm in the non‐AF group (P < 0.001). During the follow‐up period, in HCM patients with AF an increase of LA diameter and a decrease of LVEF were noted (Table 1).
Table 1.
Baseline characteristics with data for all patients and categorized according to the development of atrial fibrillation (AF)
| Variable | All patients (n = 546) | AF group (n = 141) | Non‐AF group (n = 405) | P value |
|---|---|---|---|---|
| Age (years) (mean ±SD) | 46.1 ± 13.7 | 52.7 ± 10.9 | 43.8 ± 13.8 | <0.001 |
| Family history of HCM (%) | 381 (69.8) | 101 (71.6) | 280 (69.1) | 0.58 |
| Family history of SCD (%) | 178 (32.6) | 54 (38.3) | 124 (30.6) | 0.09 |
| Presyncope/syncope (%) | 150 (27.5) | 53 (36.9) | 98 (24.2) | 0.004 |
| nsVT (%) | 311 (57) | 111 (78.7) | 200 (49.4) | <0.001 |
| Overweight (%) | 331 (60.6) | 101 (71.6) | 230 (56.8) | 0.002 |
| Obesity (%) | 120 (22) | 44 (31.2) | 76 (18.8) | 0.002 |
| BMI (kg/m2) (mean ± SD) | 26.8 ± 5.5 | 28.3 ± 5.6 | 26.2 ± 5.4 | <0.001 |
| Hypertension (%) | 204 (37.4) | 77 (54.6) | 127 (31.4) | <0.001 |
| Metabolic syndrome (%) | 231 (42.3) | 88 (62.4) | 143 (35.3) | <0.001 |
| Initial LA diameter (mm) (mean ± SD) | 39.1 ± 7.8 | 44 ± 8.1 | 37.5 ± 7 | <0.001 |
| Last LA diameter (mm) (mean ±SD) | 45.1 ± 8.6 | 51.4 ± 8.3 | 42.9 ± 7.5 | <0.001 |
| Initial EF (%) (mean ± SD) | 70.1 ± 9.5 | 69.5 ± 10.4 | 70.4 ± 9.1 | 0.28 |
| EF at the follow‐up (%) (mean ± SD) | 64.1 ± 9.5 | 59.8 ± 10.7 | 65.6 ± 8.5 | <0.001 |
| Maximal LVWT (mm) (mean ± SD) | 21.3 ± 6.2 | 21 ± 5.1 | 21.4 ± 6.5 | 0.84 |
| LVOT gradient >30 mmHg (%) | 196 (35.9) | 48 (34) | 148 (36.5) | 0.59 |
Abbreviations: HCM, hypertrophic cardiomyopathy; BMI, body mass index; LA, left atrium; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVWT, left ventricle wall thickness; ns VT, non‐sustained ventricular tachycardia; SAM, systolic anterior motion; SCD, sudden cardiac death.
3.2. Risk factors associated with presence of AF
Clinical and echocardiographic variables associated with the development of AF on univariate and multivariate analysis are presented in Table 2.
Table 2.
Univariate and multivariate logistic regression analysis variables in relation to development of atrial fibrillation (AF)
| Univariate | ||||
|---|---|---|---|---|
| Variable | P value | OR | 95% CI | |
| Age | <0.001 | 1.055 | 1.038 | 1.073 |
| Family history of HCM | 0.579 | 1.127 | 0.739 | 1.720 |
| Age ≥ 45 years | <0.001 | 4.414 | 2.807 | 6.940 |
| Family history of SCD | 0.095 | 1.407 | 0.943 | 2.098 |
| Presyncope/syncope | 0.004 | 1.830 | 1.214 | 2.760 |
| nsVT | <0.001 | 3.792 | 2.423 | 5.935 |
| BMI | <0.001 | 1.071 | 1.032 | 1.110 |
| Overweight (BMI > 25 kg/m2) | 0.002 | 1.964 | 1.271 | 3.033 |
| Hypertension | <0.001 | 2.634 | 1.779 | 3.899 |
| Initial LA | <0.001 | 1.127 | 1.094 | 1.162 |
| LA at last follow‐up | <0.001 | 1.15 | <0,001 | 1,1 |
| EF LV initially | 0.364 | 0.991 | 0.922 | 1.011 |
| EF at follow‐up | <0.001 | 0.941 | 0.922 | 0.961 |
| Maximal LVWT at follow‐up | 0.479 | 0.989 | 0.958 | 1.021 |
| SAM of mitral valve | 0.826 | 1.046 | 0.704 | 1.554 |
| LVOT gradient >30 mmHg at rest | 0.594 | 0.896 | 0.599 | 1.341 |
| LVOT gradient max | 0.126 | 0.994 | 0.958 | 1.021 |
| Multivariate | ||||
| Age ≥ 45 years | P = 0.001 | 2.382 | 1.401 | 4.049 |
| Presyncope/syncope | P = 0.002 | 2.249 | 1.354 | 3.735 |
| nsVT | P < 0.001 | 2.697 | 1.590 | 4.572 |
| LA initially | P = 0.001 | 1.065 | 1.025 | 1.106 |
| LA at last follow‐up | P < 0.001 | 1.097 | 1.058 | 1.138 |
| EF at follow‐up | P = 0.001 | 0.960 | 0.937 | 0.983 |
Abbreviations: BMI, body mass index; CI, confidence interval; HCM, hypertrophic cardiomyopathy; LA, left atrium; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVWT, left ventricle wall thickness; ns VT, non‐sustained ventricular tachycardia; OR, odds ratio; SAM, systolic anterior motion; SCD, sudden cardiac death.
Univariate analysis revealed that age, nsVT, presyncope/syncope, increased BMI, presence of hypertension, and metabolic syndrome were associated with AF development. Also, the following echocardiographic measurements were associated with AF: initial LA diameter, LA diameter at last follow‐up, and LVEF at last follow‐up. On multivariate analysis LA diameter, LVEF, age, past history of syncope/presyncope, and nsVT were all associated with AF occurrence.
LA diameter cut‐off value of 45.5 mm predicted AF development with 77% sensitivity and 68% specificity in ROC analysis (P < 0.001) (Table 3).
Table 3.
Receiver operating characteristics (ROC) curves parameters for variables significantly associated with AF
| Variable | AUC | 95%CI | Cut‐off | P value | Sensitivity | Specificity |
|---|---|---|---|---|---|---|
| Age | 0.68 | 0.64‐0.73 | 44.5 years | <0.001 | 79.4% | 53.3% |
| LA initially | 0.74 | 0.69‐0.79 | 41.5 mm | <0.001 | 65.2% | 76.0% |
| LA at last follow‐up on sinus rhythm | 0.79 | 0.74‐0.83 | 45.5 mm | <0.001 | 77.3% | 67.7% |
| LVEF at last follow‐up on sinus rhythm | 0.68 | 0.63‐0.73 | 65.5% | <0.001 | 78.6% | 50.1% |
Abbreviations: AUC, area under the curve; CI, confidence interval; LA, left atrium; LVEF, left ventricular ejection fraction.
4. DISCUSSION
Our analysis revealed that AF is present in more than a quarter of patients with HCM. AF was independently linked to age, presyncope/syncope episodes, nsVT, initial and last follow‐up LA diameter, and lower LVEF at the last follow‐up visit.
The prevalence of symptomatic or clinically silent episodes of AF in HCM patients reported in previous studies ranged from 18% to 28%.3, 4, 5, 6, 7, 8 When compared to the general population, HCM patients have a 4‐fold to 6‐fold greater likelihood of developing AF.3, 4, 5 In our study similarly to previously reported AF presence was detected in one out of four of patients with HCM.
Age is a well‐known factor associated with the risk of AF, both in the general population and in HCM patients. Maron et al reported that AF in HCM may occur at almost any age (19‐82 years) and identified age ≥ 40 years as significantly associated with AF events.5, 9 Olivotto et al confirmed that an age of >50 years at the time of diagnosis was an independent predictor of AF.4 In our cohort of HCM patients below 65, the best cutoff point (based on ROC curve) above which the risk of AF increased was 44.5 years of age.
Non‐sustained ventricular tachycardia was an independent predictor of AF in the studied group of patients. Despite controlling for these variables during statistical analysis, this may reflect the fact that patients with nsVT episodes often have more coexisting abnormalities affecting prognosis, such as greater hypertrophy, more diastolic dysfunction, greater extent of fibrosis.10 The present study identified a connection between past history of presyncope/syncope and the presence of AF. Episodes of syncope can be caused by atrial fibrillation with fast ventricular response, particularly in patients with preserved atrial function and high filling pressures, or by sustained or non‐sustained VT episodes.11 Other factors, such as severe LVOT obstruction, sinus node dysfunction, and complete atrioventricular block may also cause syncope.
Many HCM patients who experience syncope or nsVT undergo ICD implantation. Both syncope and nsVT are related to AF, as documented by our data. Some of these episodes are clinically silent.8 Hence, whenever possible, equipment with the option of LA function monitoring should be selected.
Left atrial enlargement is a known strong independent predictor of AF in HCM patients and our analysis confirmed previous results.4, 5, 12, 13, 14 Interestingly, LA diameter at the initial evaluation was associated with AF presence. Our results confirm that the atrial diameter of 45.5 mm is a predictor of AF. A meta‐analysis of studies including 7381 HCM patients13 showed that those with AF had a larger LA diameter compared to patients without AF (45.37 vs 38.03 mm). Based on the results of various studies, the generally accepted LA size predisposing to AF is ≥45 mm.
Previous research has shown that HCM patients with AF have lower EF.3 This may of course be either a primary or a secondary phenomenon. Our data indicate that moderate LVEF deterioration may actually precede AF in these patients. This may reflect an early phase of deleterious mechanisms, such as myocardial fibrosis.
Metabolic syndrome, hypertension and obesity are all well documented risk factors of AF.15, 16, 17, 18 Pedrosa et al have demonstrated that LA diameter is correlated to BMI value in HCM patients.19 Furthermore, the risk of AF increases by about 8% along with BMI increase by 1kg/m2, 18 Our results also show that metabolic syndrome, hypertension and obesity are common among patients with AF, however they were not independent risk factors in the studied cohort.
Studies that assessed the effect of LVOT obstruction on the prevalence of AF yield contradictory results. We have not found it to be an independent AF risk factor. Autore et al observed that the incidence of AF was significantly higher among patients with LVOT obstruction.20 During 10‐year follow‐up, the cumulative risk of AF was at the level of 43% in patients with obstruction and 18% in those without.20 Another study in patients undergoing alcohol septal ablation (ASA) revealed that those who developed AF had significantly lower values of LVOT gradient after ASA (P ≤ 0.005).21 In a recent study, Lu et al found that significant left ventricular outflow gradient was related to a combined endpoint, a part of which was new onset AF.22 However, a provoked gradient between 30 and 89 mmHg was related to a lower risk of the combined endpoint occurrence. The discrepancy in these and other studies might be caused by the fact that the LVOT gradient is a dynamic, variable parameter changing over time and depending on various factors, both associated with patient's physiological condition and the measurement itself. In our study LVOT gradient was not predictive for AF presence.
In our cohort, almost 69.8% HCM patients had a positive family history, while 32.6% had a family history of SCD. This is admittedly more than in most other cohorts.3, 4, 23 A reason for this may be the fact that we are a referral center, actively screening even distantly living families of HCM patients referred to us. As a referral center we have a cohort of higher risk patients, often those after SCD in their family, referred for further diagnosis and ICD implantation.
4.1. Limitations
As this was a retrospective study, we may not infer on any causal relationships. This was a single center study and the observations were made across a significant time period. Some results may therefore be more variable than had they been obtained within a shorter time (different equipment, treatment regimen, etc.).
5. CONCLUSIONS
Our study indicates that AF is a common complication of HCM. Therefore, it is important to assess risk factors predisposing to the development of atrial fibrillation in each patient with HCM. Patients with high AF risk may be identified using features such as older age, LA > 45.5 mm, nsVT and previous occurrence of presyncope/syncope.
Conflict of interest
The authors declare no potential conflict of interests.
Klopotowski M, Kwapiszewska A, Kukula K, et al. Clinical and echocardiographic parameters as risk factors for atrial fibrillation in patients with hypertrophic cardiomyopathy. Clin Cardiol. 2018;41:1336–1340. 10.1002/clc.23050
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