Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website http://www.cardiologyres.org

Original Article

Volume 10, Number 5, October 2019, pages 268-277

Excessive Atrial Ectopic Activity Worsens Prognosis and Predicts the Type of Major Adverse Cardiac Events in Patients With Frequent Premature Ventricular Contractions

Figure 1. ROC curve survival analysis by PAC number. PAC: premature atrial contraction; ROC: receiver operator characteristic.

Figure 2. Kaplan-Meier estimates for the primary end points. Overall survival in patients with and without EAEA (a), overall survival in patients with and without NSVT (b), AF free survival in patients with and EAEA (c), stroke free survival in patients with and without EAEA (d). EAEA: excessive atrial ectopic activity; NSVT: non-sustained ventricular tachycardia.

Figure 3. Kaplan-Meier estimates for the secondary end points. Survival free from HF death or HF hospitalizations in patients with and without EAEA (a), survival free from HF death or HF hospitalizations in patients with and without NSVT (b), survival free from arrhythmic death or VA hospitalizations in patients with and without EAEA (c), survival free from arrhythmic death or VA hospitalizations in patients with and without NSVT (d). EAEA: excessive atrial ectopic activity; HF: heart failure; NSVT: non-sustained ventricular tachycardia; VA: ventricular arrhythmia.

**Table 1.** Baseline Characteristics in the Two Groups With and Without EAEA
	Overall sample (n = 285)	EAEA (-) (n = 158)	EAEA (+) (n = 127)	P value^c
Values are presented as median (interquartile range) or n (%). ^aThe CHA₂DS₂VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, transitory ischemic attack or thromboembolism (2 points); vascular disease (history of MI, vascular disease or aortic atherosclerosis) (1 point); age 65 - 74 years (1 point) and female gender (1 point). ^bClass I or class III antiarrhythmics. ^cP values were calculated using Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. EAEA: excessive atrial ectopic activity; NSVT: non-sustained ventricular tachycardia; PVC: premature ventricular contraction; PAC: premature atrial contraction; AV: atrioventricular; LAD: left atrium diameter; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVFS: left ventricular fractional shortening.
Demographic data
Age (years)	68 (60 - 76)	62 (53 - 73)	74 (66 - 79)	< 0.0001
Male gender, n (%)	171 (60)	92 (58)	79 (62)	0.544
Risk factors
Diabetes, n (%)	66 (26)	35 (26)	31 (27)	0.887
Hypertension, n (%)	216 (86)	108 (80)	108 (93)	0.003
Dyslipidemia, n (%)	143 (57)	78 (58)	65 (56)	0.799
High CHA₂DS₂VASc^a	191(76)	87 (64)	104 (90)	< 0.0001
Previous stroke, n (%)	39 (14)	19 (12)	20 (15)	0.390
Etiology
Structural heart disease, n (%)	118 (41)	67 (42)	51 (40)	0.718
Ischemic heart disease n (%)	86 (30)	49 (73)	37 (73)	0.999
Medications
Beta-blockers, n (%)	106 (37)	67 (42)	39 (31)	0.049
Antiarrhythmics^b, n (%)	16 (6)	8 (5)	8 (6)	0.797
24 - h Holter recording
Maximal heart rate (bpm)	113 (100 - 126)	115 (102 - 126)	109 (98 - 128)	0.048
Minimal heart rate (bpm)	49 (43 - 54)	49 (44 - 55)	48 (42 - 53)	0.153
Mean heart rate (bpm)	71 (64 - 79)	73 (65 - 81)	69 (63 - 78)	0.035
Number of PVCs/day	2,776 (1,594 - 7,025)	3,475 (1,623 - 8,402)	2,461 (1,526 - 4,790)	0.038
Polymorphic morphology, n (%)	192 (69%)	94 (61)	98 (81)	< 0.0001
NSVT, n (%)	54 (19)	25 (16)	29 (23)	0.171
Number of PACs/day	48 (7 - 445)	11 (1 - 29)	636 (167 - 2,900)	< 0.0001
Supraventricular runs, n (%)	92 (32)	22 (14)	70 (55)	< 0.0001
AV node conduction disease, n (%)	49 (17)	24 (15)	25 (20)	0.346
Echocardiogram
LAD (mm)	37 (35 - 42)	40 (35 - 45)	38 (35 - 43)	0.004
LVDD (mm)	53 (49 - 58)	51 (48 - 56)	55 (50 - 59)	0.029
LVSD (mm)	34 (30 - 40)	33 (30 - 40)	35 (30 - 40)	0.325
LVFS (%)	36 (30 - 40)	36 (28 - 40)	36 (30 - 40)	0.975
Follow-up in years	8.4 (5.1 - 10)	8.7 (7.6 - 10.3)	7.6 (3.9 - 9.6)	< 0.0001

Table 1. Baseline Characteristics in the Two Groups With and Without EAEA

Overall sample (n = 285)

EAEA (-) (n = 158)

EAEA (+) (n = 127)

P value^c

Values are presented as median (interquartile range) or n (%). ^aThe CHA₂DS₂VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, transitory ischemic attack or thromboembolism (2 points); vascular disease (history of MI, vascular disease or aortic atherosclerosis) (1 point); age 65 - 74 years (1 point) and female gender (1 point). ^bClass I or class III antiarrhythmics. ^cP values were calculated using Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. EAEA: excessive atrial ectopic activity; NSVT: non-sustained ventricular tachycardia; PVC: premature ventricular contraction; PAC: premature atrial contraction; AV: atrioventricular; LAD: left atrium diameter; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVFS: left ventricular fractional shortening.

Demographic data

Age (years)

68 (60 - 76)

62 (53 - 73)

74 (66 - 79)

< 0.0001

Male gender, n (%)

171 (60)

92 (58)

79 (62)

0.544

Risk factors

Diabetes, n (%)

66 (26)

35 (26)

31 (27)

0.887

Hypertension, n (%)

216 (86)

108 (80)

108 (93)

0.003

Dyslipidemia, n (%)

143 (57)

78 (58)

65 (56)

0.799

High CHA₂DS₂VASc^a

191(76)

87 (64)

104 (90)

< 0.0001

Previous stroke, n (%)

39 (14)

19 (12)

20 (15)

0.390

Etiology

Structural heart disease, n (%)

118 (41)

67 (42)

51 (40)

0.718

Ischemic heart disease n (%)

86 (30)

49 (73)

37 (73)

0.999

Medications

Beta-blockers, n (%)

106 (37)

67 (42)

39 (31)

0.049

Antiarrhythmics^b, n (%)

16 (6)

8 (5)

8 (6)

0.797

24 - h Holter recording

Maximal heart rate (bpm)

113 (100 - 126)

115 (102 - 126)

109 (98 - 128)

0.048

Minimal heart rate (bpm)

49 (43 - 54)

49 (44 - 55)

48 (42 - 53)

0.153

Mean heart rate (bpm)

71 (64 - 79)

73 (65 - 81)

69 (63 - 78)

0.035

Number of PVCs/day

2,776 (1,594 - 7,025)

3,475 (1,623 - 8,402)

2,461 (1,526 - 4,790)

0.038

Polymorphic morphology, n (%)

192 (69%)

94 (61)

98 (81)

< 0.0001

NSVT, n (%)

54 (19)

25 (16)

29 (23)

0.171

Number of PACs/day

48 (7 - 445)

11 (1 - 29)

636 (167 - 2,900)

< 0.0001

Supraventricular runs, n (%)

92 (32)

22 (14)

70 (55)

< 0.0001

AV node conduction disease, n (%)

49 (17)

24 (15)

25 (20)

0.346

Echocardiogram

LAD (mm)

37 (35 - 42)

40 (35 - 45)

38 (35 - 43)

0.004

LVDD (mm)

53 (49 - 58)

51 (48 - 56)

55 (50 - 59)

0.029

LVSD (mm)

34 (30 - 40)

33 (30 - 40)

35 (30 - 40)

0.325

LVFS (%)

36 (30 - 40)

36 (28 - 40)

36 (30 - 40)

0.975

Follow-up in years

8.4 (5.1 - 10)

8.7 (7.6 - 10.3)

7.6 (3.9 - 9.6)

< 0.0001

**Table 2.** Baseline Characteristics in the Patients With and Without NSVT
	Overall sample (n = 285)	NSVT (+) (n = 54)	NSVT (-) (n = 231)	P value^c
Values are presented as median (interquartile range) or n (%). ^aThe CHA₂DS₂VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, transitory ischemic attack or thromboembolism(2 points); vascular disease (history of MI, vascular disease or aortic atherosclerosis) (1 point); age 65 - 74 years (1 point) and female gender (1 point). ^bClass I or class III antiarrhythmics. ^cP values were calculated using Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. EAEA: excessive atrial ectopic activity (> 70 PACs/day); SHD: structural heart disease; IHD: ischemic heart disease; NSVT: non-sustained ventricular tachycardia; PVC: premature ventricular contraction; PAC: premature atrial contraction; AV: atrioventricular; LAD: left atrium diameter; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVFS: left ventricular fractional shortening.
Demographic
Age (years)	68 (60 - 76)	68 (61 - 76)	68 (60 - 76)	0.986
Male gender, n (%)	171 (60)	43 (80)	128 (55)	0.001
Risk factors
Diabetes, n (%)	66 (26)	11 (23)	55 (27)	0.715
Hypertension, n (%)	216 (86)	41 (87)	175 (86)	0.9999
Dyslipidemia, n (%)	143 (57)	27 (57)	116 (57)	0.9999
High CHA₂DS₂VASc^a	191(76)	40 (87)	151 (74)	0.082
Previous stroke, n (%)	39 (14)	7 (13)	32 (14)	0.999
Etiology
SHD, n (%)	118 (41)	19 (35)	148 (64%)	< 0.0001
IHD n (%)	86 (30)	23 (34)	63 (76)	0.266
Medications
Beta-blockers, n (%)	106 (37)	21 (39)	85 (37)	0.876
Antiarrhythmics^b, n (%)	16 (6)	1 (2)	15 (7)	0.322
24 - h Holter recording
Maximal heart rate (bpm)	113 (100 - 126)	113 (102 - 126)	113 (100 - 125)	0.573
Minimal heart rate (bpm)	49 (43 - 54)	51 (44 - 56)	48 (43 - 53)	0.097
Mean heart rate (bpm)	71 (64 - 79)	76 (65 - 82)	70 (64 - 78)	0.088
Number of PVC/day	2,776 (1,594 - 7,025)	3,573 (1,758 - 11,600)	2,589 (1,564 - 6,172)	0.068
Polymorphic, n (%)	192 (69%)	46 (89)	146 (66)	0.001
PAC > 70/day n (%)	127 (44)	29 (54)	98 (43)	0.171
Number of PACs/day	48 (7 - 445)	86 (6 - 1,092)	46 (7 - 382)	0.587
Supraventricular runs, n (%)	92 (32)	16 (30)	76 (33)	0.447
AV node disease, n (%)	49 (17)	12 (22)	37 (16)	0.316
Echocardiogram
LAD (mm)	37 (35 - 42)	41 (36 - 45)	38 (35 - 44)	0.007
LVDD (mm)	53 (49 - 58)	55 (52 - 63)	51 (48 - 57)	< 0.0001
LVSD (mm)	34 (30 - 40)	35 (30 - 48)	33 (30 - 39	0.004
LVFS (%)	36 (30 - 40)	34 (24 - 40)	36 (30 - 40)	0.081
Follow-up in years	8.4 (5.1 - 10)	7.8 (3.8 - 9.5)	8.6 (5.5 - 10)	0.026

Table 2. Baseline Characteristics in the Patients With and Without NSVT

Overall sample (n = 285)

NSVT (+) (n = 54)

NSVT (-) (n = 231)

P value^c

Values are presented as median (interquartile range) or n (%). ^aThe CHA₂DS₂VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, transitory ischemic attack or thromboembolism(2 points); vascular disease (history of MI, vascular disease or aortic atherosclerosis) (1 point); age 65 - 74 years (1 point) and female gender (1 point). ^bClass I or class III antiarrhythmics. ^cP values were calculated using Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. EAEA: excessive atrial ectopic activity (> 70 PACs/day); SHD: structural heart disease; IHD: ischemic heart disease; NSVT: non-sustained ventricular tachycardia; PVC: premature ventricular contraction; PAC: premature atrial contraction; AV: atrioventricular; LAD: left atrium diameter; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVFS: left ventricular fractional shortening.

Demographic

Age (years)

68 (60 - 76)

68 (61 - 76)

68 (60 - 76)

0.986

Male gender, n (%)

171 (60)

43 (80)

128 (55)

0.001

Risk factors

Diabetes, n (%)

66 (26)

11 (23)

55 (27)

0.715

Hypertension, n (%)

216 (86)

41 (87)

175 (86)

0.9999

Dyslipidemia, n (%)

143 (57)

27 (57)

116 (57)

0.9999

High CHA₂DS₂VASc^a

191(76)

40 (87)

151 (74)

0.082

Previous stroke, n (%)

39 (14)

7 (13)

32 (14)

0.999

Etiology

SHD, n (%)

118 (41)

19 (35)

148 (64%)

< 0.0001

IHD n (%)

86 (30)

23 (34)

63 (76)

0.266

Medications

Beta-blockers, n (%)

106 (37)

21 (39)

85 (37)

0.876

Antiarrhythmics^b, n (%)

16 (6)

1 (2)

15 (7)

0.322

24 - h Holter recording

Maximal heart rate (bpm)

113 (100 - 126)

113 (102 - 126)

113 (100 - 125)

0.573

Minimal heart rate (bpm)

49 (43 - 54)

51 (44 - 56)

48 (43 - 53)

0.097

Mean heart rate (bpm)

71 (64 - 79)

76 (65 - 82)

70 (64 - 78)

0.088

Number of PVC/day

2,776 (1,594 - 7,025)

3,573 (1,758 - 11,600)

2,589 (1,564 - 6,172)

0.068

Polymorphic, n (%)

192 (69%)

46 (89)

146 (66)

0.001

PAC > 70/day n (%)

127 (44)

29 (54)

98 (43)

0.171

Number of PACs/day

48 (7 - 445)

86 (6 - 1,092)

46 (7 - 382)

0.587

Supraventricular runs, n (%)

92 (32)

16 (30)

76 (33)

0.447

AV node disease, n (%)

49 (17)

12 (22)

37 (16)

0.316

Echocardiogram

LAD (mm)

37 (35 - 42)

41 (36 - 45)

38 (35 - 44)

0.007

LVDD (mm)

53 (49 - 58)

55 (52 - 63)

51 (48 - 57)

< 0.0001

LVSD (mm)

34 (30 - 40)

35 (30 - 48)

33 (30 - 39

0.004

LVFS (%)

36 (30 - 40)

34 (24 - 40)

36 (30 - 40)

0.081

Follow-up in years

8.4 (5.1 - 10)

7.8 (3.8 - 9.5)

8.6 (5.5 - 10)

0.026

**Table 3.** Events per 1,000 Person-Years According to the Presence of EAEA or NSVT
	Overall sample	EAEA (-)	EAEA (+)	P value^a
All-cause death	55	36.8	83.2	< 0.0001
Stroke	8.8	2.3	18.8	< 0.0001
New-onset AF	29.7	16.9	49.2	< 0.0001
HF death or HF hospitalizations	7	0.8	16.4	< 0.0001
Arrhythmic death or VA hospitalizations	6	5.4	7	0.661
Values are presented in number of events per 1,000 person-years. AF; atrial fibrillation; HF: heart failure; VA: ventricular arrhythmia; EAEA: excessive atrial ectopic activity; EAEA excessive atrial ectopic activity; NSVT: non-sustained VT episodes; NSVT: non-sustained VT episodes. ^aP values were calculated using the Log-rank test.
All-cause death	55	50.5	78	0.047
Stroke	8.8	7.2	16.6	0.670
New-onset AF	29.7	27.2	42	0.052
HF death or HF hospitalizations	7	4.4	19.5	0.002
Arrhythmic death or VA hospitalizations	6	5.5	16.8	0.003

Table 3. Events per 1,000 Person-Years According to the Presence of EAEA or NSVT

Overall sample

EAEA (-)

EAEA (+)

P value^a

2,158 person-years

1,305 person-years

853 person-years

All-cause death

36.8

83.2

< 0.0001

Stroke

8.8

2.3

18.8

< 0.0001

New-onset AF

29.7

16.9

49.2

< 0.0001

HF death or HF hospitalizations

0.8

16.4

< 0.0001

Arrhythmic death or VA hospitalizations

5.4

0.661

Overall sample

NSVT (-)

NSVT (+)

P value^a

2,158 person-years

1,800 person-years

358 person-years

Values are presented in number of events per 1,000 person-years. AF; atrial fibrillation; HF: heart failure; VA: ventricular arrhythmia; EAEA: excessive atrial ectopic activity; EAEA excessive atrial ectopic activity; NSVT: non-sustained VT episodes; NSVT: non-sustained VT episodes. ^aP values were calculated using the Log-rank test.

All-cause death

50.5

0.047

Stroke

8.8

7.2

16.6

0.670

New-onset AF

29.7

27.2

0.052

HF death or HF hospitalizations

4.4

19.5

0.002

Arrhythmic death or VA hospitalizations

5.5

16.8

0.003

**Table 4.** Cox Regression Models Showing the Hazard Ratio of Number of PACs, and Presence of NSVT in Relation to the Primary and Secondary End Points
End points	Unadjusted	Adjusted
^aHR adjusted to age, CHA₂DS₂VASc score, presence of SHD, beta-blocker therapy,new-onset AF, LAD and LVFS. ^bHR adjusted to age, CHA₂DS₂VASc score, previous stroke, LAD and new-onset AF. ^cHR adjusted to age, hypertension, diabetes, beta-blocker therapy, presence of SHD and LAD. ^dHR adjusted to the presence of age, SHD, beta-blocker therapy, new-onset AF and LVFS. ^eHR adjusted to the presence of age, beta-blocker therapy, structural heart disease and LVFS. ^fP values were calculated using the Cox proportional-hazards model. PAC: premature atrial contraction; AF: atrial fibrillation; HF: heart failure; VA: ventricular arrhythmia; NSVT: non-sustained ventricular tachycardia; LAD: left atrium diameter; LVFS: left ventricular fractional shortening; SHD: structural heart disease.
Log₂ number of PACs/day
All - cause death	1.131 (1.080 - 1.084)	< 0.0001	1.077 (1.014 - 1.145)^a	0.017
Stroke	1.321 (1.163 - 1.501)	< 0.0001	1.250 (1.080 - 1.447)^b	0.003
New-onset AF	1.193 (1.117 - 1.275)	< 0.0001	1.090 (1.006 - 1.181)^c	0.036
HF death or HF hospitalizations	1.287 (1.119 - 1.482)	< 0.0001	1.376 (1.128 - 1.679)^d	0.002
Arrhythmic death or VA hospitalizations	1.080 (0.941 - 1.240)	0.273	-
NSVT
All - cause death	1.530 (1.001 - 2.337)	0.049	1.584 (0.990 - 2.534)^a	0.055
HF death or HF hospitalizations	4.255 (1.542 - 11.74)	0.005	1.519 (0.497 - 4.643)^c	0.464
Arrhythmic death or VA hospitalizations	4.424 (1.484 - 13.19)	0.008	3.644 (1.147 - 11.57)^e	0.028

Table 4. Cox Regression Models Showing the Hazard Ratio of Number of PACs, and Presence of NSVT in Relation to the Primary and Secondary End Points

End points

Unadjusted

Adjusted

HR (95% CI)

P value

HR (95% CI)

P value^f

^aHR adjusted to age, CHA₂DS₂VASc score, presence of SHD, beta-blocker therapy,new-onset AF, LAD and LVFS. ^bHR adjusted to age, CHA₂DS₂VASc score, previous stroke, LAD and new-onset AF. ^cHR adjusted to age, hypertension, diabetes, beta-blocker therapy, presence of SHD and LAD. ^dHR adjusted to the presence of age, SHD, beta-blocker therapy, new-onset AF and LVFS. ^eHR adjusted to the presence of age, beta-blocker therapy, structural heart disease and LVFS. ^fP values were calculated using the Cox proportional-hazards model. PAC: premature atrial contraction; AF: atrial fibrillation; HF: heart failure; VA: ventricular arrhythmia; NSVT: non-sustained ventricular tachycardia; LAD: left atrium diameter; LVFS: left ventricular fractional shortening; SHD: structural heart disease.

Log₂ number of PACs/day

All - cause death

1.131 (1.080 - 1.084)

< 0.0001

1.077 (1.014 - 1.145)^a

0.017

Stroke

1.321 (1.163 - 1.501)

< 0.0001

1.250 (1.080 - 1.447)^b

0.003

New-onset AF

1.193 (1.117 - 1.275)

< 0.0001

1.090 (1.006 - 1.181)^c

0.036

HF death or HF hospitalizations

1.287 (1.119 - 1.482)

< 0.0001

1.376 (1.128 - 1.679)^d

0.002

Arrhythmic death or VA hospitalizations

1.080 (0.941 - 1.240)

0.273

NSVT

All - cause death

1.530 (1.001 - 2.337)

0.049

1.584 (0.990 - 2.534)^a

0.055

HF death or HF hospitalizations

4.255 (1.542 - 11.74)

0.005

1.519 (0.497 - 4.643)^c

0.464

Arrhythmic death or VA hospitalizations

4.424 (1.484 - 13.19)

0.008

3.644 (1.147 - 11.57)^e

0.028