One hundred thirty six patients were included to the study. The flowchart in Fig. 1 shows the study cohort, inclusion and exclusion, as well as the numbers of patients during follow-up. General patient characteristics and confounding factors are summarized in Table 1. The most important characteristics of subarachnoid hemorrhage in the entire cohort is shown in Table 2. In the entire cohort endovascular treatment was performed in 73, surgical clipping in 21 patients, in 42 patients no intervention was performed. A placement of an intraventricular drain was necessary in 40 cases, whereas lumbar drain was placed in 5 cases.
Table 1
General characteristics and confounding factors in the entire cohort
Parameter | Value |
Age (years) | 76.2 (48–72) |
Gender (F/M) | 80/56 |
Hypertension (Yes/No) | 73/63 |
Arrhytmias or conduction disturbances (Yes/No) | 4/132 |
Hypercholesterinemia/Trigliceridaemia (Yes/No) | 15/121 |
Diabetes mellitus (Yes/No) | 5/131 |
Hypothyreosis (Yes/No) | 3/133 |
Hyperthyreosis (Yes/No) | 1/132 |
Smoking (Yes/No) | 66/70 |
Obesity (Yes/No) | 33/103 |
Table 2
Characteristics of subarachnoid hemorrhage in the entire cohort
Location of the aneurysm ‡ | |
Internal carotid | 20 |
Anterior and middle cerebral | 30 |
Anterior and posterior communicating | 47 |
Other | 17 |
No aneurysm | 22 |
Ventricular bleeding (Yes/No) | 69/83 |
Parenchymal bleeding (Yes/No) | 27/109 |
Bleeding extent (side) | |
Left | 11 |
Right | 14 |
Bilateral | 2 |
No bleeding | 109 |
Bleeding location (lobe) | |
Frontal | 10 |
Frontotemporal | 3 |
Temporal | 7 |
Temporoparietal | 7 |
None | 109 |
Modified Fisher score at admission | |
1 | 31 |
2 | 19 |
3 | 27 |
4 | 59 |
Hunt-Hess grade at admission | |
1 | 23 |
2 | 37 |
3 | 31 |
4 | 21 |
5 | 24 |
WFNS score at admission | |
1 | 62 |
2 | 18 |
3 | 7 |
4 | 26 |
5 | 23 |
GCS at admission | |
3–4 | 11 |
5–6 | 12 |
7–8 | 16 |
9–12 | 10 |
13–14 | 25 |
15 | 62 |
The incidence of TTC in the studied cohort
Takotsubo cardiomyopathy developed in 39 of the 136 patients (28.7 %). TTC was mild or severe in 28 (20.6%) and 11 (8.1%) patients, respectively.
The distribution of the different patterns according to the recommendation (2) was as follows: classical pattern: n = 10; mid-ventricular pattern: n = 1; reverse pattern: n = 4; focal type: n = 21; atypical pattern (global): n = 3. TTC developed within 7 days after admission in 4 cases, all were focal type.
The effect of age and gender on the occurence and severity of TTC
The occurrence of TTC was not related to the age of the patients (binomial logistic regression, odds ratio: 1.015, z = 0.821, p = 0.412). Similarly, the severity of TTC was not related to patient age (ordinal logistic regression, coefficient = 0.013 ± S.E. 0.018, odds ratio: 1.013, t = 0.729, p = 0.466).
Takotsubo cardiomyopathy was more frequent in females (30/39; 77%) than in males (9/39; 23%). TTC occurred in 30 (37.5%) of the 80 female patients and in 9 (16%) out of the 56 male patients. The difference was statistically significant (Yates-corrected χ2 = 6.385, df = 1, p = 0.012. TTC appeared to be more severe in female patients: 23 (29%) presented with mild and 7 (9%) with severe TTC, compared to male patients: 5 (9%) mild and 4 (7%) severe TTC cases, respectively (χ2 = 8.152, simulated p = 0.015).
The effect of comorbidities on the occurrence of TTC
The occurrence of TTC was not influenced by any of the comorbidities studied (Supplemental Table 1). A binomial logistic regression calculated in a general linear model testing the effect of each additional illness on the occurrence of TTC (yes/no) found that none of the eight illnesses/conditions influenced the occurrence of TTC (data not shown).
The relationship between comorbidities and severity of TTC
The severity of TTC was not influenced by any of the comorbidities studied (Supplemental Table 2). An ordinal logistic regression calculated in a general linear model testing the effect of each additional illness on the severity of TTC (none, mild, severe) found that none of the eight illnesses influenced the severity of TTC (data not shown).
The relationship between the occurrence of TTC and the severity scores at admission
The incidence of TTC was related to the modified Fisher scores; it increased from 13% in patients with Fisher score of 1 to 16% in score 2, 30% in score 3; 41% in patients with score 4 (Table 3). The occurrence of TTC also increased with WFNS score from 18% in patients with score 1 and 14% in score 3 patients to 39% in score 2, 35% in score 4 and 48% in score 5 patients (Table 3). None of the other variables influenced the occurrence of TTC (Table 3).
Table 3
Occurrence of TTC in SAV variable categories. Significant variables are highlighted in Bold.
SAV variable | No TTC | TTC | χ2 |
Location of aneurysm ‡ | | | |
Internal carotid | 12 | 8 | |
Anterior and middle cerebral | 24 | 6 | 2.984 n.s. |
Anterior and posterior communicating | 32 | 15 | |
Other | 12 | 5 | |
No aneurysm | 17 | 5 | |
Ventricular bleeding (Y/N) | 46/51 | 23/16 | 1.059 n.s. |
Parenchymal bleeding (Y/N) | 21/76 | 6/33 | 0.349 n.s. |
Bleeding extent (side) | | | |
Left | 8 | 3 | 1.311 n.s. |
Right | 11 | 3 | |
Bilateral | 2 | 0 | |
No bleeding | 76 | 33 | |
Bleeding location (lobe) | | | |
Frontal | 7 | 3 | 2.060 n.s. |
Frontotemporal | 3 | 0 | |
None | 76 | 33 | |
Temporal | 5 | 2 | |
Temporoparietal | 6 | 1 | |
Hunt-Hess grade | | | |
1 | 18 | 5 | 6.856 n.s. |
2 | 31 | 6 | |
3 | 19 | 12 | |
4 | 15 | 6 | |
5 | 14 | 10 | |
Modified Fisher score | | | |
1 | 27 | 4 | 9.481 * |
2 | 16 | 3 | p = 0.024 |
3 | 19 | 8 | |
4 | 35 | 24 | |
WFNS | | | |
1 | 51 | 11 | 9.823 * |
2 | 11 | 7 | p = 0.041 |
3 | 6 | 1 | |
4 | 17 | 9 | |
5 | 12 | 11 | |
GCS | | | |
3–4 | 6 | 5 | |
5–6 | 6 | 6 | |
7–8 | 13 | 3 | 13.509 * |
9–12 | 4 | 6 | p < 0.05 |
13–14 | 17 | 8 | |
15 | 51 | 11 | |
Note: * p < 0.05; n.s. indicates non-significant difference |
‡ neighbouring values or similar categories were pooled to meet χ2-test assumptions |
Relationship between severity of TTC and severity scores at admission
The severity of TTC was related to modified Fisher score, Hunt-Hess score, WFNS score and GCS (Table 4). The incidence of mild TTC was 13%, 11%, 26% and 25% in patients with modified Fisher score of 1, 2, 3 and 4, respectively, whereas the incidence of severe TTC increased from 0 in patients with score 1 to 5% in score 2, 4% in score 3 and 15% in score 4 patients (Table 4).
Table 4
Severity of TTC in different SAH variable categories. Significant effects are highlighted in Bold.
SAV variable | No TTC (n = 97) | Mild TTC (n = 28) | Severe TTC (n = 11) | χ2 |
Location of aneurysm ‡ | | | | 3.836 n.s. |
Internal carotid | 12 | 5 | 3 |
Middle and anterior cerebral | 24 | 4 | 2 |
Anterior and posterior communicating | 32 | 11 | 4 |
Other | 12 | 4 | 1 |
No aneurysm | 17 | 4 | 1 | |
Ventricular bleeding (Y/N) | 46/51 | 14/14 | 9/2 | 4.684 n.s. |
Parenchymal bleeding (Y/N) | 21/76 | 4/24 | 2/9 | 0.761 n.s. |
Bleeding side | | | | 1.392 n.s. |
Left | 8 | 2 | 1 |
Right | 11 | 2 | 1 |
Bilateral | 2 | 0 | 0 |
No bleeding | 76 | 24 | 9 |
Bleeding extent (lobe) | | | | |
Frontal | 7 | 2 | 1 | 2.779 n.s. |
Frontotemporal | 3 | 0 | 0 |
None | 76 | 24 | 9 |
Temporal | 5 | 1 | 1 |
Temporoparietal | 6 | 1 | 0 |
Hunt-Hess grade | | | | 22.687 ** p = 0.004 |
1 | 18 | 5 | 0 |
2 | 31 | 6 | 0 |
3 | 19 | 9 | 3 |
4 | 15 | 5 | 1 |
5 | 14 | 3 | 7 |
Modified Fisher score | | | | 12.668 * p = 0.047 |
1 | 27 | 4 | 0 |
2 | 16 | 2 | 1 |
3 | 19 | 7 | 1 |
4 | 35 | 15 | 9 |
WFNS score | | | | |
1 | 51 | 11 | 0 | 24.258 ** p = 0.003 |
2 | 11 | 5 | 2 |
3 | 6 | 1 | 0 |
4 | 17 | 7 | 2 |
5 | 12 | 4 | 7 |
GCS | | | | 22.616 *** p = 0.001 |
3–6 | 12 | 4 | 7 |
7–12 | 17 | 7 | 2 |
13–14 | 17 | 6 | 2 |
15 | 51 | 11 | 0 |
Note: * p < 0.05; ** p < 0.01; *** p < 0.001 |
‡ neighbouring values or similar categories were pooled to meet χ2-test assumptions |
The incidence of mild TTC varied between 13% (Hunt-Hess score 5) and 29% (H-H score 3) with no obvious trend, whereas the incidence of severe TTC increased from 0 in patients with scores 1 and 2 to 10% in score 3, 5% in score 4 and 29% in score 5 patients (Table 4). The incidence of mild TTC also varied between 17% and 28% in the five WFNS score groups, while the incidence of severe TTC increased from 0 in scores 1 and 3 to 11% in score 2, 8% in score 4 and 30% in score 5 (Table 4). Finally, the incidence of severe TTC was highest (30%) in GCS scores 3 to 6, was lower in scores 7 to 12 and 13 to 14 (8% each) was 0 in score 15; mild TTC varied in frequency between 17 and 27% with no obvious trend (Table 4).
When the effects of all SAV variables were tested simultaneously in a binomial logistic regression followed by backward stepwise removal of non-significant effects, only the modified Fisher score influenced the incidence of TTC, and a positive coefficient indicated that TTC was more likely to occur in patients with higher modified Fisher scores (estimate: 0.54 ± S.E. 0.185, odds ratio: 1.719, z = 2.923, p = 0.003). Similarly, the severity of TTC showed a positive relationship with only the modified Fisher score (estimate: 0.57 ± 0.185, odds ratio: 1.764, z = 3.071, p = 0.036).
Relationship between development of vasospasm and TTC:
Vasospasm (any type) occurred in 23/97 patients in the control (non TTC) group and 13/39 in the TTC group (Chi2:0.74; P = 0.36), indicating that TS was not more frequent in SAH patients in whom vasospasm developed. Severe vasospasm occurred in 5/97 patients and 6/39 patients in the non-TTC and TTC groups, respectively (Chi2:2,87; p = 0.09.)
Laboratory parameters
For CK, the differences between the three groups were significant on day 1 (Kruskal-Wallis χ2 = 11.642, df = 2, p = 0.003), day 2 (χ2 = 8.673, df = 2, p = 0.013) and day 4 (χ2 = 7.478, df = 2, p = 0.024) but not on the other days. For CK-MB, the differences were significant on day 1 (χ2 = 9.346, df = 2, p = 0.009), but not on the other days. For CTNT, the differences were highly significant each day, mostly because of high values in the severe TTC group (Fig. 2).
For NTPBNP, the differences were also highly significant each day because of high values in the severe TTC group (Fig. 3)
General linear models showed that the level of metanephrin in the urine did not differ between the three study groups and was not influenced by the level of arterenol or dobutamin administered, and this was true for the day of admission, as well as days 30 and 180 of follow up (results not shown). In contrast, the level of normetanephrin differed between TTC groups and was influenced by arterenol and dobutamin administration (Fig. 4, Supplemental Table 3). The interaction between groups and arterenol or dobutamin were not significant (results not shown), indicating that the effects of the drugs were similar in each group. The difference between study groups was marginally non-significant 30 days after the bleeding, partly due to a slight difference between the control and the mild TTC group and partly due to few data in the severe TTC group (Fig. 4B, Supplemental Table 3). Finally, there was no difference in normetanephrin concentration between the study groups 180 days after the bleeding (GLM, F2,54 = 0.209, p = 0.812).
Changing the echocardiography parameters over time
The ejection fraction was significantly lower in patients with severe TTC than in non-TTC controls, and was intermediate but closer to level of controls in patients in patients with mild on both day 1 and 7 (Fig. 5A-D). These differences were marginally significant on day 30 and disappeared by day 180. Thus, ejection fraction improved stepwise in TTC patients during the follow-up period, but there were still signs of weak contractile function.
The wall motion score index was highest in patients in the severe TTC group, and low in the mild TTC and control groups (Fig. 5E-H). The differences were significant on all study days, indicating that the difference could be detected even after 180 days.
Relationship between severity of TTC and mortality
By the end of the follow-up period (180 days), 70 (74.5%) patients survived in the control (non-TTC) group (n = 94), 22 (81.5%) survived in the mild TTC group (n = 27) and three (27%) survived in the severe TTC group (n = 11). The difference in mortality rate was significant (χ2 = 12.395, df = 2, p = 0.002). The number of deceased patients during different phases of follow up were as follows:
-
Days 1–7: NoTTC group: n = 9; mild TTC: n = 2, severe TTC: n = 6
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Days 8–30: No TTC: n = 6; mild TTC: n = 3; severe TTC: n = 1
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Days 31–180: No TTC: n = 9; mild TTC: n = 0; severe TTC: n = 1
Relationship between the severity of TTC and the outcome of the patients
GOS, Barthel, and Karnofsky outcome scores were higher in patients in the control (non-TTC) and the mild TTC groups than in the severe TTC group (Fig. 6.). All the differences were significant, with the exception of the differences in Barthel scores during the second check-up (Fig. 6E), indicating that severe TTC is associated with worse long-term clinical outcome of the patients.