As shown in Table 1, a total of 189 cases were included for analysis, among whom median age was 53 (38, 62) years and of whom 52.9% (100/189) were female. Surprisingly, PPGLs were incidentally found in 59.3% (112/189) of patients, among whom no symptoms occurred or, in symptomatic cases, symptoms were not considered to be related to space-occupying effect of tumors or CAs-related effect (data not shown). Hypertension occurred in 97 (51.3%) subjects, and sustained pattern (52/97, 53.6%) dominated over paroxysmal (15/97, 15.5%), mixed (19/97, 19.6%), and unknown (11/97, 11.3%) pattern. With regard to symptoms documented in medical records, abdominal discomfort (nausea or vomiting), chest pain, dyspnea and classic triad symptoms (headache, palpitation, and/or profuse sweating) appeared in 9.5% (18/189), 3.2% (6/189), 14.8% (28/189) and 8.5% (16/189) of included subjects, respectively. Troponin (55/189, 29.1%) and NT-proBNP (51/189, 27.0%) were tested in only approximately one-quarter of study subjects, perhaps due to that only patients suspicious of cardiac damage were screened. 70 (37.0%) patients were screened for CAs secretion of tumors, as plasma CAs/MNs test was unavailable until January 2018 in our center; however, urine vanillylmandelic acid test was performed in 103 (54.5%) cases, resulting in 135 (71.4%) patients undergoing at least one of the aforementioned endocrine tests. The majority of patients received urine routine examination (185/189, 97.9%), ECG examination (182/189, 96.3%), blood count examination (187/189, 98.9%), and renal function examination (188/189, 99.5%). Of note, invasive behavior and the presence of hemorrhage/necrosis on pathology reports were described in 29.7% and 20.0% of subjects, respectively.
Table 1
Clinical profiles of patients diagnosed with PPGLs and comparisons between ACCs group and non-ACCs group.
|
All
(n = 189)
|
non-ACCs
(n = 175)
|
ACCs
(n = 14)
|
P value
|
Male
|
89 (47.1)
|
79 (45.1)
|
10 (71.4)
|
0.058
|
Age (years)
|
53 (38, 62)
|
54 (38, 62)
|
48 (38, 52)
|
0.320
|
History of hypertension
|
97 (51.3)
|
86 (49.1)
|
11 (78.6)
|
0.034
|
Patterns of hypertension (n = 97)
|
|
|
|
0.266
|
sustained
|
52 (53.6)
|
49 (57.0)
|
3 (27.3)
|
paroxysmal
|
15 (15.5)
|
13 (15.1)
|
2 (18.2)
|
mixed
|
19 (19.6)
|
15 (17.4)
|
4 (36.4)
|
unknown
|
11 (11.3)
|
9 (10.5)
|
2 (18.2)
|
|
Symptoms
|
|
|
|
|
nausea or vomiting
|
18 (9.5%)
|
11 (6.3)
|
7 (50.0)
|
< 0.001
|
presence of chest pain
|
6 (3.2)
|
4 (2.3)
|
2 (14.3)
|
0.065
|
presence of dyspnea
|
28 (14.8)
|
14 (8.0)
|
14 (100)
|
< 0.001
|
presence of triad&
|
16 (8.5)
|
15 (8.6)
|
1 (7.1)
|
1.000
|
ECG changes (n = 182)
|
|
|
|
|
ST-segment changes
|
19 (10.4)
|
15 (8.9)
|
4 (28.6)
|
0.043
|
T wave inversion
|
29 (15.3)
|
22 (13.1)
|
7 (50.0)
|
0.002
|
Blood parameters
|
|
|
|
|
hemoglobin (g/L) (n = 187)
|
132.8 ± 20.7
|
132.5 ± 20.2
|
136.8 ± 26.4
|
0.452
|
platelet count (× 109/L) (n = 187)
|
256.1 ± 81.5
|
251.9 ± 76.6
|
308. 6 ± 118.5
|
0.100
|
white blood cell count (× 109/L) (n = 187)
|
6.6 (5.5, 8.6)
|
6.4 (5.4, 8.1)
|
15.6 (12.1, 18.9)
|
< 0.001
|
eGFR (ml/min/1.73 m2) (n = 188)
|
108.0 (96.9, 117.8)
|
108.0 (97.4, 117.8)
|
106.1 (49.3, 117.3)
|
0.408
|
Positive urine protein (n = 185)
|
24 (13.0)
|
19 (11.1)
|
5 (35.7)
|
0.026
|
Cardiac biomarkers
|
|
|
|
|
elevation of troponin (n = 55)
|
19 (34.5)
|
6 (14.3)
|
13 (100)
|
< 0.001
|
elevation of NT-proBNP* (n = 51)
|
20 (39.2)
|
7 (18.4)
|
13 (100)
|
< 0.001
|
Patterns of secretion (n = 70)
|
|
|
|
|
unknown
|
4 (5.7)
|
4 (6.8)
|
0 (0)
|
|
without endocrine
|
12 (17.1)
|
12 (20.3)
|
0 (0)
|
0.044
|
epinephrine predominant
|
5 (7.1)
|
4 (6.8)
|
1 (9.1)
|
norepinephrine predominant
|
25 (35.7)
|
23 (39.0)
|
2 (18.2)
|
a combination of both
|
24 (34.3)
|
16 (27.1)
|
8 (72.7)
|
Patterns of secretion (n = 70)
|
|
|
|
|
epinephrine secretion
|
29 (41.4)
|
20 (33.9)
|
9 (81.8)
|
0.006
|
Tumor characteristics
|
|
|
|
|
paragangliomas
|
52 (27.5)
|
50 (28.6)
|
2 (14.3)
|
0.357
|
bilateral adrenal tumors (n = 137)
|
6 (4.4)
|
5 (4.0)
|
1 (8.3)
|
0.429
|
right adrenal tumors (n = 137)
|
70 (51.1)
|
64 (51.2)
|
6 (50.0)
|
0.937
|
maximal tumor diameters (cm)
|
4.5 (3.2, 6)
|
4.5 (3, 6)
|
5.5 (4.7, 6.5)
|
0.053
|
invasive behavior at histology (n = 185)
|
55 (29.7)
|
47 (27.3)
|
8 (61.5)
|
0.022
|
hemorrhage/necrosis at histology (n = 185)
|
37 (20.0)
|
30 (17.4)
|
7 (53.9)
|
0.005
|
Continuous variables are expressed as mean ± standard deviation or median (25th, 75th percentage); categorical variables are presented as number and percentages in parentheses. Missing data varied by variables. |
Abbreviations: ACCs: acute cardiac complications; cm: centimeter; ECG: electrocardiography; eGFR: estimated glomerular filtration rate; NT-proBNP: N-terminal pro-B type natriuretic peptide. |
&defined as presentation of headache, palpitation, and/or profuse sweating. |
*defined as NT-proBNP on admission equal to or greater than 125 pg/Ml. |
Acute cardiac complications
As depicted in Table 2, fourteen (7.4%) patients suffered ACCs, including nine cases (4.8%) with Takotsubo-like cardiomyopathy, three cases (1.6%) with heart failure with preserved ejection fraction (HFpEF) and one case (0.5%) with catecholamine-induced cardiomyopathy. Two patients displayed recurrent episodes of Takotsubo-like cardiomyopathy, of whom one (case 10, two times) with 2 years apart and one (case 9, three times) with 4 years apart. Predisposing factors were identified in only six (42.9%) cases, consisting of physical activity or defecation in three cases, operation in one, pregnancy in one and respiratory tract infection in the remaining one. In addition, labile blood pressure was detected in five patients (35.7%). As for the location of the tumors, diagnoses of PGLs were made in only two cases. In the eleven patients who were screened for plasma catecholamine levels, the pattern of a combination of both (8/11, 72.7%) dominated over the pattern of epinephrine predominance (1/11, 9.1%) and norepinephrine predominance (2/11, 18.2%). All thirteen patients with biomarkers for cardiac injuries displayed elevated troponin T (median 437.6 pg/ml) and NT-proBNP (median 8946 pg/ml). The mean of left ventricular ejection fraction (LVEF) in acute phase was 0.45, with a range of 0.21–0.65; notably, the LVEF reached the normal range by 6–30 days in all nine patients diagnosed with Takotsubo-like cardiomyopathy. Due to the familial PHEOs and other endocrine glands involvement, case 4 was diagnosed with multiple endocrine neoplasia type 2 without genetic testing. Case 14 was a mid-aged male patient and underwent re-echocardiography examination at 10 months after surgery, which showed no recovery of LVEF, leading to the diagnosis of catecholamine-induced cardiomyopathy.
Table 2
Characteristics of patients with ACCs.
Case
|
Sex/age
(years)
|
Initial symptoms
|
Triggers
|
Labile
blood pressure
|
Location of tumors
|
Plasma catecholamine (× ULN)
|
Troponin
(pg/ml)
|
NT-proBNP
(pg/ml)
|
ECG
|
E/MN
|
NE/NMN
|
1
|
51/male
|
nausea, vomiting, dyspnea, palpitation
|
physical activity
|
no
|
left adrenal PHEO
|
5.9
|
2.5
|
1159
|
> 35000
|
sinus tachycardia, ST depression and T inversion in V4 − 6
|
2
|
38/male
|
nausea, vomiting, dyspnea, palpitation, headache
|
physical activity
|
no
|
bilateral adrenal PHEO
|
15.8
|
4.2
|
1220
|
5976
|
ST depression and T inversion in V1 − 6, prolonged QTc interval
|
3
|
16/female
|
dyspnea
|
infection
|
no
|
right adrenal PHEO
|
normal
|
> 12.1
|
19.3
|
2985
|
sinus tachycardia
|
4
|
47/male
|
dyspnea, palpitation, sweating
|
no
|
yes
|
right adrenal PHEO
|
4.0
|
normal
|
2773
|
25492
|
sinus tachycardia, nonspecific T wave changes
|
5
|
49/female
|
dyspnea
|
no
|
no
|
left adrenal PHEO
|
11.2
|
11.9
|
77.3
|
4740
|
T wave inversion in inferior leads
|
6
|
62/male
|
dyspnea, palpitation, sweating
|
no
|
no
|
left adrenal PHEO
|
2.6
|
57.5
|
84.3
|
7976
|
diminished R wave in V2 − 3
|
7
|
51/male
|
dyspnea, chest pain
|
operation
|
no
|
right adrenal PHEO
|
-
|
-
|
130.2
|
2250
|
premature atrial complex
|
8
|
66/female
|
nausea, vomiting, dyspnea, sweating
|
defecation
|
yes
|
right adrenal PHEO
|
-
|
-
|
437.6
|
33914
|
T wave inversion in inferior leads and V2 − 6
|
9
|
29/male
|
nausea, dyspnea, palpitation, sweating
|
no
|
yes
|
left adrenal PHEO
|
8.4
|
11.4
|
663.6
|
26508
|
sinus tachycardia, second degree AVB
|
10
|
76/male
|
nausea, vomiting, dyspnea
|
no
|
no
|
right adrenal PHEO
|
9.4
|
2.9
|
2178
|
> 35000
|
sinus tachycardia, low voltage in limb leads, ST depression in V3 − 6
|
11
|
35/female
|
dyspnea, palpitation, sweating
|
pregnancy
|
yes
|
retroperitoneal PGL
|
-
|
-
|
-
|
-
|
T wave inversion in inferior leads and V3 − 6
|
12
|
46/male
|
nausea, vomiting, dyspnea, headache
|
no
|
yes
|
right adrenal PHEO
|
25.1
|
16.0
|
121.9
|
8946
|
T wave inversion in I, aVL, and V6
|
13
|
42/male
|
nausea, vomiting, dyspnea, chest pain, headache
|
no
|
no
|
left adrenal PHEO
|
10.4
|
7.6
|
954.2
|
12913
|
ST depression in inferior leads and V4 − 6, ST elevation in aVR
|
14
|
52/male
|
dyspnea
|
no
|
no
|
pelvic PGL
|
normal
|
> 12.1
|
72.1
|
1208
|
sinus tachycardia, LBBB
|
Table 2
Characteristics of patients with ACCs (continued).
Case
|
Acute LVEF (%)
|
Strain analysis
|
Impaired patterns in LS
|
Acute global LS
|
Coronary
artery evaluation
|
Recovery
on imaging
|
Clinical diagnosis
|
1
|
0.38
|
yes
|
apical ballooning
|
-5.5
|
CTA: (-)
|
6 days
|
Takotsubo syndrome
|
2
|
0.39
|
yes
|
apical sparing
|
-10.7
|
CAG: (-)
|
7 days
|
Takotsubo syndrome
|
3
|
0.45
|
yes
|
apical sparing
|
-4.8
|
without risk factors
|
30 days
|
Takotsubo syndrome
|
4
|
0.21
|
yes
|
apical sparing
|
-6.1
|
without risk factors
|
14 days
|
Takotsubo syndrome
|
5
|
0.62
|
no
|
-
|
-
|
CAG: (-)
|
-
|
HFpEF
|
6
|
0.64
|
yes
|
apical sparing
|
-16.8
|
CTA: (-)
|
-
|
HFpEF
|
7
|
0.43
|
no
|
-
|
-
|
CTA: p-RCA 50% stenosis
|
12 days
|
Takotsubo syndrome
|
8
|
0.61
|
no
|
-
|
-
|
no
|
-
|
HFpEF, ischemic stroke
|
9
|
0.36
|
no
|
-
|
-
|
without risk factors
|
11 days
|
Recurrent Takotsubo syndrome (3 times)
|
10
|
0.38
|
yes
|
segmental
|
-21.2
|
CTA: (-)
|
11 days
|
Recurrent Takotsubo syndrome (2 times)
|
11
|
0.65
|
no
|
-
|
-
|
without risk factors
|
-
|
HFpEF
|
12
|
0.59
|
yes
|
apical sparing
|
-9.6
|
without risk factors
|
7 days
|
Takotsubo syndrome
|
13
|
0.35
|
yes
|
apical sparing
|
-13.6
|
CAG: (-)
|
15 days
|
Takotsubo syndrome
|
14
|
0.28
|
yes
|
global
|
-
|
CAG: (-)
|
without recovery in 10 months
|
Catecholamine-induced cardiomyopathy
|
Abbreviations: AVB: atrioventricular block; CAG: coronary artery angiography; CTA: coronary computed tomography angiography; E: epinephrine; HFpEF: heart failure with preserved ejection fraction; LBBB: left bundle branch block; LVEF: left ventricular ejection fraction; LS: longitudinal strain; LV: left ventricle; MN: metanephrine; NE: norepinephrine; NMN: normetanephrine; PGL: paraganglioma; PHEO: pheochromocytoma; p-RCA: proximal right coronary artery; ULN: upper limit of normal. Other abbreviations as shown in Table 1. |
In comparison to non-ACCs group, ACCs group shared similar characteristics in sex (male, 71.4% vs 45.1%, P = 0.058) and age (median, 48 vs 54, P = 0.320). As expected, more patients with ACCs had hypertension (78.6% vs 49.1%, P = 0.034); however, the patterns of hypertension didn’t differ in two groups (P = 0.266). Surprisingly, the proportions of subjects who displayed classic triad symptoms (7.1% vs 8.6%, P = 1.000) and chest pain (14.3% vs 2.3%, P = 0.065) were similar and quite low among two groups; nevertheless, much more patients showed gastrointestinal symptoms (50.0% vs 6.3%, P < 0.001) and dyspnea (100% vs 8.0%, P < 0.001) in ACCs group. Expectedly, with regard to ECG changes, patients with ACCs were more prevalent in both ST-segment changes (28.6% vs 8.9%, P = 0.043) and T wave inversions (50.0% vs 13.1%, P = 0.002) as compared to those without ACCs. In terms of laboratory findings, proteinuria was more likely to be prevalent in ACCs group (35.7% vs 11.1%, P = 0.026); likewise, ACCs group had higher median level of white blood cell (median, 15.6 vs 6.4, P < 0.001). Additionally, as for patterns of secretion, a combination of both dominated in patients with ACCs (P = 0.044); moreover, a higher prevalence of epinephrine-producing PPGLs (81.8% vs 33.9%. P = 0.006) was observed in ACCs group. Overall, the proportions of paragangliomas, bilateral adrenal tumors, and right adrenal tumors were similar between two groups; however, patients with ACCs exhibited a trend for having larger maximal tumor diameters, but the difference didn’t reach statistical significance (median, 5.5 vs 4.5, P = 0.053). Interestingly, more patients in ACCs group showed invasive behavior (61.5% vs 27.3%, P = 0.022) and hemorrhage/necrosis (53.9% vs 17.4%, P = 0.005) on pathology report as compared with patients in non-ACCs group.
Strain analysis
As shown in Table 2, 2D strain analysis was carried out in 9 (64.3%) out of 14 patients with ACCs, and technical reasons accounted for the failure of analysis in the rest 5 cases. Strikingly, 6 (66.7%) patients displayed the pattern of relative apical sparing in LS; meanwhile, of the rest 3 patients, one (case 1) showed the pattern of apical ballooning, one (case 10) displayed the pattern of segmental dysfunction, and the last one (case 14) showed the pattern of global dysfunction. Of 7 patients with Takotsubo-like cardiomyopathy who underwent strain analysis, one patient (case 1) (14.3%) exhibited the typical apical ballooning pattern; however, 5 (71.4%) (case 2, 3, 4, 12, 13) cases showed the pattern of relative apical sparing in LS. Visual examples of patterns of ‘apical ballooning’, ‘apical sparing’, ‘global’ and ‘segmental’ in LS are depicted in Fig. 1 (panel A-G). Finally, the mean value of GLS was − 11.0 ± 5.8, with a range of -5.5 to -21.2.
Subclinical myocardial injuries
The prevalence of SMIs was potential to be underestimated owing to unthorough investigations or to be an overestimation because of the prescription of examinations being at discretion of physicians in this study. Only 74 (39.2%) patients had echocardiography examination, 55 (29.1%) received troponin test and 51 (27.0%) underwent NT-proBNP test; then, only 91 (48.2%) patients received at least one of the aforementioned three examinations. After excluding patients with ACCs, 21 (27.2%) cases out of 77 experienced SMIs, including elevated NT-proBNP in 15, elevated troponin in 4 and abnormal findings on echocardiography examinations in 10 patients (shown in Table 3).
Table 3
Characteristics of patients with SMIs.
Case
|
Sex/age
(years)
|
Location of tumors
|
Blood catecholamine (× ULN)
|
Troponin
(pg/ml)
|
NT-proBNP
(pg/ml)
|
Echocardiography
|
Impaired patterns on strain analysis*
|
E/MN
|
NE/NMN
|
1
|
55/male
|
retroperitoneal PGL
|
normal
|
15.3
|
normal
|
normal
|
enlarged LA and LV, LVH
|
anterior and lateral segments
|
2
|
35/female
|
right adrenal PHEO
|
normal
|
33.1
|
-
|
-
|
LVH
|
apical sparing
|
3
|
31/male
|
retroperitoneal PGL
|
-
|
-
|
21.4
|
216.4
|
LVH
|
-
|
4
|
56/male
|
retroperitoneal PGL
|
normal
|
12.2
|
337.4
|
137.2
|
normal
|
normal
|
5
|
47/female
|
left adrenal PHEO
|
-
|
-
|
normal
|
350
|
enlarged LA
|
-
|
6
|
58/female
|
left adrenal PHEO
|
9.1
|
2.7
|
normal
|
366.6
|
normal
|
apical sparing
|
7
|
38/male
|
left adrenal PHEO
|
normal
|
> 12.1
|
normal
|
164.2
|
enlarged LA, LVH
|
anterior and lateral segments
|
8
|
65/male
|
retroperitoneal PGL
|
-
|
-
|
21
|
2140
|
-
|
-
|
9
|
70/male
|
left adrenal PHEO
|
4.9
|
4.8
|
-
|
-
|
normal
|
basal inferior segment
|
10
|
54/female
|
right adrenal PHEO
|
-
|
-
|
normal
|
153
|
normal
|
anterior and lateral segments
|
11
|
54/female
|
right adrenal PHEO
|
38.9
|
12.1
|
normal
|
778.4
|
LVH
|
-
|
12
|
67/female
|
left adrenal PHEO
|
normal
|
5.2
|
-
|
-
|
enlarged LA, LVH
|
anterior and lateral segments
|
13
|
31/male
|
left adrenal PHEO
|
normal
|
8.4
|
normal
|
303.8
|
-
|
-
|
14
|
39/female
|
left adrenal PHEO
|
7.6
|
9.9
|
normal
|
1008
|
normal
|
|
15
|
67/male
|
right adrenal PHEO
|
2.8
|
7.4
|
-
|
-
|
segmental dysfunction, enlarged LA
|
anterior and lateral segments
|
16
|
56/female
|
right adrenal PHEO
|
4.0
|
1.9
|
normal
|
322.6
|
-
|
-
|
17
|
55/female
|
right adrenal PHEO
|
normal
|
normal
|
-
|
-
|
pulmonary hypertension
|
anterior segment
|
18
|
35/female
|
right adrenal PHEO
|
4.0
|
4.0
|
normal
|
408.5
|
-
|
-
|
19
|
23/male
|
right adrenal PHEO
|
normal
|
8.5
|
normal
|
337.7
|
-
|
-
|
20
|
57/female
|
right adrenal PHEO
|
normal
|
normal
|
48.39
|
215.8
|
-
|
-
|
21
|
40/female
|
left adrenal PHEO
|
-
|
-
|
normal
|
770
|
-
|
-
|
Abbreviations: LA: left atrium; LVH: left ventricular hypertrophy. Other abbreviations as shown in Tables 1 and 2. |
* not all patients with echocardiography examinations were suitable for two-dimension strain analysis. |