Where There's Smoke, There's Fire? Significance of Atrial Fibrillation in Young Patients

ABSTRACT

Background

Atrial fibrillation (AF), a disease of the elderly, occasionally occurs at younger age. Pathophysiology of AF in younger patients is diverse, including channelopathies and cardiomyopathies. Data on the significance and complications of AF in young patients are scarce.

Hypothesis

Atrial fibrillation is the first manifestation of cardiovascular disease (CVD) in young patients.

Methods

From 11 888 patients in a university hospital database, patients age ≤35 years were identified. A composite of stroke/transient ischemic attack, thromboembolic events, major bleeding, and death was the primary endpoint. Stroke/transient ischemic attack, thromboembolic events, major bleeding, death, AF during follow‐up, diagnosis of arrhythmia other than AF, and new diagnosis of any CVD were secondary endpoints.

Endpoints were compared between patients with and without comorbidities.

Results

We identified 124 patients (29.1± 5 years). Of those, 84 were followed over 48.4 ± 39.8 months. Comorbidities were present in 40.5%. Incidence of the primary endpoint was not different between the groups. Arrhythmias other than AF were more common in patients without comorbidities (36% vs 14.7%; P = 0.032). A supraventricular tachycardia (SVT) was found in 57.1% of patients who underwent electrophysiological testing and was treated with catheter ablation. None of those patients had AF during follow‐up.

Conclusions

Atrial fibrillation occurs in young patients with and without structural heart disease. Young AF patients without comorbidities rarely develop CVD during the first years after diagnosis. Yet, an SVT is found in a high proportion of young AF patients; AF may be first manifestation of SVT. Therefore, young patients should undergo further evaluation for SVT

Introduction

Atrial fibrillation (AF), the most common cardiac arrhythmia in adults, is usually prevalent in patients age ≥60 years.1 However, a number of patients with AF are presenting with the first episode at younger age.2 In contrast to older patients, where fibrosis, atrial dilation, and oxidative stress are key mechanisms,3, 4, 5, 6 pathophysiology of AF in younger patients is diverse. Causes for AF in the young include ion‐channel disease, cardiomyopathy, and genetic factors.7, 8, 9, 10 Particularly, the role of AF as a first manifestation of a clinically silent cardiac disease has been discussed.11, 12 Furthermore, the course and complications of AF in daily practice have not been investigated for younger patients. Because the prevalence of AF in persons age <40 years is 0.5%,2 the absolute number of young patients in different studies and registries is low and data on AF in persons age <35 years are scarce. The purpose of our study was to evaluate the clinical significance of AF in young adults.

Methods

From 11 888 patients with AF who presented to the university arrhythmia center at the Charité–Universitätsmedizin Berlin between January 2001 and December 2014, all patients age ≤35 years were analyzed. The study complies with the Declaration of Helsinki and was approved by the ethics committee of the Charité–Universitätsmedizin Berlin.

At baseline, AF type according to actual guidelines and symptoms using the European Heart Rhythm Association (EHRA) classification, comorbidities, treatment strategy (rate vs rhythm control), anticoagulant treatment, stroke, and bleeding risk were assessed. Stroke and bleeding risk were determined using the CHA₂DS₂‐VASc and HAS‐BLED scores, respectively. A composite of stroke/transient ischemic attack (TIA), thromboembolic events, major bleeding, and death from any cause was the primary endpoint. Follow‐up visits were scheduled at the discretion of the treating physician but at least once a year. Stroke/TIA, thromboembolic events, major bleeding, death, AF during follow‐up, diagnosis of arrhythmia other than AF, and new diagnosis of any cardiovascular disease were secondary endpoints. Endpoints were assessed both at scheduled an unscheduled visits during follow‐up.

Statistical Analysis

Discrete variables are presented as numbers and percentages; continuous variables are presented as mean and SD. The Mann‐Whitney U test (for skewed data) or the t test were used as appropriate for comparison of continuous variables. The χ² test was used to analyze discrete variables. All analyses were performed using SPSS software version 22.0 (IBM Corp., Armonk, NY). A P value of <0.05 was considered statistically significant.

Results

A total of 11 888 patients that presented to our hospital center between January 2001 and December 2014 were included in the registry. Of those, 124 (1.04%) were age ≤35 years at the time of their first presentation, with a mean age of 29.1 5 years. Patient characteristics and medications are presented in Table 1.

Table 1.

Patient Baseline Characteristics

Characteristic	Value
No. of patients	124
Mean age, y	29.1 ± 5
Male sex	93 (75)
BMI, kg/m2	25.9 ± 5
LVEF, %	54 ± 12.1
HR, min−1	99.4 ± 39.7
SBP, mm Hg	122.8 ± 19.3
DBP, mm Hg	72.8 ± 12
CHA2DS2‐VASc	0.7 ± 1
HAS‐BLED	0.5 ± 0.6
Rhythm control	56 (45.2)
EHRA class
I	68 (54.8)
II	45 (36.3)
III	9 (7.3)
IV	2 (1.6)
AF without comorbidity	53 (42.7)
AF type
First diagnosed AF	26 (21)
Paroxysmal AF	62 (50)
Persistent AF	17 (13.7)
Permanent AF	3 (2.4)
Unknown	16 (12.9)
Comorbidities
HTN	22 (17.7)
CAD	3 (2.4)
HF	14 (11.3)
Cardiomyopathy	24 (19.4)
Previous stroke or TIA	6 (4.8)
DM	2 (1.6)
Hyperlipoproteinemia	5 (4)
COPD	1 (0.8)
Carcinoma	6 (4.8)
Impaired renal function	7 (5.6)
Smoker	14 (11.3)
Medication
Flecainide	13 (10.5)
Propafenone	2 (1.6)
Amiodarone	5 (4)
Dronedarone	2 (1.6)
Sotalol	1 (0.8)
Verapamil	2 (1.6)
β‐Blocker	80 (64.5)
Digitalis	5 (4)
ACEI	29 (23.4)
ARB	6 (4.8)
Statin	3 (2.4)
ASA	31 (25)
Clopidogrel	4 (3.2)
OAC
Vitamin K antagonist	36 (29)
Factor Xa inhibitor	9 (7.3)

Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ASA, aspirin; BMI, body mass index; CAD, coronary artery disease; CHA₂DS₂‐VASc, congestive heart failure, HTN, age ≥75 y, DM, stroke/TIA, vascular disease, age 65–74 y, sex category (women); COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; DM, diabetes mellitus; EHRA, European Heart Rhythm Association; HAS‐BLED, hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, elderly (age ≥65), drug therapy; HF, heart failure; HR, heart rate; HTN, hypertension; INR, international normalized ratio; LVEF, left ventricular ejection fraction; OAC, oral anticoagulation; SBP, systolic blood pressure; SD, standard deviation; TIA, transient ischemic attack.

Data are presented as n (%) or mean ± SD.

Of all patients, 42.7% had AF in the absence of any comorbidity. The majority of patients had first diagnosed (21%) or paroxysmal AF (50%). In our center, 45.2% of the patients presented with symptoms, mainly in EHRA class II. Rhythm control was chosen as the treatment strategy in 56 (45.2%) of the patients. In CHA₂DS₂‐VASc and HAS‐BLED were 0.7 ± 1 and 0.5 ± 0.6, respectively. Forty‐five patients (36.3%) received oral anticoagulation.

Follow‐up Results

Of all patients from this age group, 84 were followed over 48.4 ± 39.8 months, with 8.2 ± 8.8 visits during follow‐up. During follow‐up, 8 (9.5%) patients reached the primary composite endpoint. Four patients experienced a major bleeding (1 massive groin hematoma after catheter ablation, 1 pulmonary bleeding due to pneumonia with respiratory failure, 1 hemorrhagic ovarian cyst, and 1 intra‐abdominal bleeding after abdominal surgery). Two patients died during follow‐up (1 heart failure due to hypertrophic cardiomyopathy, 1 pneumonia with respiratory failure). Arrhythmias other than AF were observed in 27.4%. Stroke/TIA and heart failure systemic embolism were not observed during the study. In none of the patients was a cardiovascular disease newly diagnosed during follow‐up. Complete results for primary and secondary endpoints are presented in Table 2.

Table 2.

Outcome During Follow‐up

	Outcome During Follow‐up, n = 84
Rhythm‐control strategy	42 (50)
OAC	34 (40.5)
Composite endpoint (stroke/TIA, SE, major bleeding, death)	8 (9.5)
Stroke/TIA	—
SE	—
Major bleeding	4 (4.8)
Death	2 (2.4)
AF at follow‐up	23 (27.4)
Arrhythmia other than AF	23 (27.4)
New diagnosis of CVD	—

Abbreviations: AF, atrial fibrillation; CVD, cardiovascular disease; OAC, oral anticoagulants; SE, systemic embolism; TIA, transient ischemic attack.

Data are presented as n (%).

Further analysis revealed significant differences between patients with AF associated with cardiovascular comorbidities compared with those with without comorbidities (Table 3). The CHA₂DS₂‐VASc and HAS‐BLED scores were lower in patients without comorbidities. Yet, in this cohort of young patients, score values were low in both groups and no significant differences in oral anticoagulation treatment were found.

Table 3.

Outcome During Follow‐up Compared Between Patients With AF Associated With Cardiovascular Comorbidities vs AF Patients Without Comorbidities

	AF Associated With Comorbidities, n = 34	AF Without Comorbidities, n = 50	P Value
CHA2DS2‐VASc score	1 ± 1.1	0.3 ± 0.6	<0.001a
HAS‐BLED score	0.7 ± 0.7	0.4 ± 0.5	0.023a
Comorbidities
CAD	2 (5.9)	—
HTN	13 (38.2)	—
Mechanical valve replacement	6 (17.6)	—
Hypertrophic cardiomyopathy	7 (20.6)	—
Dilated cardiomyopathy	3 (8.8)	—
Takotsubo cardiomyopathy	2 (5.9)	—
Arrhythmogenic RV cardiomyopathy	1 (2.9)	—
Other cardiomyopathy	7 (20.6)	—
Anticoagulation	17 (50)	17 (34)	0.14
Vitamin K antagonist	15 (44.1)	13 (26)
Factor Xa inhibitor	2 (5.9)	4 (8)
Rhythm control	20 (58.8)	34 (68)	0.39
Electrical cardioversion	13	17
Antiarrhythmic drugs	11	8
Catheter ablation	8	21
Study endpoints
Composite endpoint	5 (14.7)	3 (6)	0.18
Stroke/TIA	—	—
SE	—	—
Major bleeding	2 (5.9)	2 (4)	0.69
Death	2 (5.9)	—	0.049a
AF at follow‐up	13 (38.2)	10 (20)	0.66
Arrhythmia other than AF	5 (14.7)	18 (36)	0.032a
Typical atrial flutter (ambulatory ECG)	3 (8.8)	6 (12)	0.64
VT (ambulatory ECG)	1 (2.9)	—	0.22
Induced SVT during electrophysiology study	1 (2.9)	12 (24)	0.009a
AV reentry tachycardia	1	4
AV node reentry tachycardia	—	8
New diagnosis of CVD	—	—	NA

Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; CHA₂DS₂‐VASc, congestive heart failure, HTN, age ≥75 y, DM, stroke/TIA, vascular disease, age 65–74 y, sex category (women); CVD, cardiovascular disease; DM diabetes mellitus; ECG, electrocardiogram; HAS‐BLED, hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, elderly (age ≥65), drug therapy; HTN, hypertension; INR, international normalized ratio; NA, not applicable; RV, right ventricular; SD, standard deviation; SE, systemic embolism; SVT, supraventricular tachycardia; TIA, transient ischemic attack; VT, ventricular tachycardia.

Data are presented as n (%) or mean ± SD.

^aStatistically significant.

Arrhythmias other than AF were more common in patients without comorbidities (36% vs 14.7%), with a proportion of 24% having a supraventricular tachycardia (SVT), namely AV reentry tachycardia (AVRT) or AV node reentry tachycardia (AVNRT; Table 3). Diagnosis of SVT in those patients was confirmed during electrophysiology study and successfully treated with catheter ablation in all cases.

Two patients died, both from the group of patients with comorbidities (1 heart failure, 1 pneumonia). No case of unexplained death occurred in any of the groups, nor was an ion‐channel disease diagnosed during follow‐up. One case of sustained ventricular tachycardia was observed. The patient had been diagnosed with hypertrophic cardiomyopathy earlier and was treated with an implantable cardioverter‐defibrillator.

Discussion

We present data on the incidence and complications of AF in patients ≤35 years. Atrial fibrillation is associated with structural heart disease in this age group in 57.3% of the patients. Incidence of stroke or systemic embolism is low in patients with and without comorbidities. Yet, death and major bleeding occurred in 2.4% and 4.8%, respectively.

Surprisingly, a relatively high incidence of arrhythmia other than AF (27.4%) was observed during follow‐up. Subgroup analysis of patients with and without comorbidities revealed that 36% of patients without comorbidities had an arrhythmia other than AF during follow‐up. In patients without comorbidities undergoing electrophysiology testing, an SVT was found in 57.1% of the cases.

It has been previously proposed that AF in the absence of overt cardiac disease may be the first manifestation of another underlying disease (eg, an ion‐channel disease [Brugada syndrome], long QT syndrome) or a cardiomyopathy.11, 12, 13 None of the patients in our study was newly diagnosed with a channelopathy or a cardiomyopathy during follow‐up. No sudden or unexplained death occurred. In contrast, a relatively high incidence of SVT was observed in patients undergoing electrophysiology testing and catheter ablation. In fact, in 12 of 21 patients without comorbidities (57.1%) who underwent catheter ablation, an SVT was detected. Unlike typical atrial flutter, which is found in a high proportion of AF patients,14 young patients with SVT only rarely present with AF episodes. An association of SVT and AF is reported in the literature.15, 16, 17 However, patients with SVT and AF are usually older than the patients in our study, and AF is more common in patients with AVRT compared with AVNRT.15, 16 The patients undergoing electrophysiology testing in our study were originally referred to our center for pulmonary vein isolation (PVI) as treatment of AF. The AVRT or AVNRT were diagnosed during routine diagnostic tests at the beginning of the procedure. When diagnosis of SVT was confirmed, ablation of accessory pathway or slow pathway modification was performed and AF was not targeted in the ablation procedure. Patients were discharged without further treatment for AF. None of the patients undergoing catheter ablation of SVT had recurrence of any arrhythmia during follow‐up. Therefore, AF may be triggered by SVT episodes and secondary to the underlying SVT in those patients. Yet, we cannot rule out coincidence of AF and SVT in those patients. The rationale for treatment of SVT rather than PVI was to start with a relatively short and safe procedure in these cases and decide the need for PVI based on the clinical follow‐up.

Notably, we cannot rule out presence of SVT as trigger for AF in the vast majority of patients, because we did not routinely perform electrophysiology studies in our cohort. To our concern, it is of high clinical interest to determine the presence of AVRT or AVNRT in this special subset of AF patients. Young patients with AF secondary to SVT, once treated with catheter ablation, may never have episodes of any arrhythmia again. Others may have coincidentally SVT and AF. The latter may require further treatment for AF despite successful ablation of SVT, including anticoagulant treatment as appropriate and PVI. In any case, thorough diagnostic testing is required before young AF patients are referred for PVI, as complication rates for PVI are much higher than for SVT ablation. A PVI must be avoided in those patients who do not need it. An electrophysiology study may be considered in the routine workup in patients age ≤35 years without comorbidities who present with recurrent episodes of AF.

Study Limitations

There are limitations to our study that should be acknowledged. First, nonrandomized observational protocol was used. Second, the number of patients in follow‐up is relatively small, and a number of patients were lost to follow‐up. It would be particularly interesting to ascertain whether these patients did not present to follow‐up visits because they had no recurrence of AF.

Conclusion

Atrial fibrillation occurs in young patients with and without structural heart disease. An SVT is found in a high proportion of young AF patients without structural heart disease. Atrial fibrillation, therefore, may be the first manifestation of SVT. Because curative treatment for SVT, in contrast to AF, is straightforward, young AF patients should undergo further evaluation for SVT.