Speckle tracking analysis allows sensitive detection of stress cardiomyopathy in severe aneurysmal subarachnoid hemorrhage patients
Stress cardiomyopathy is a common life-threatening complication after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that left ventricular (LV) longitudinal strain alterations assessed with speckle tracking could identify early systolic function impairment.
This was an observational single-center prospective pilot controlled study conducted in a neuro-intensive care unit. Forty-six patients with severe SAH with a World Federation of Neurological Surgeons grade (WFNS) ≥III were included. Transthoracic echocardiography (TTE) was performed on day 1, day 3, and day 7 after the patient’s admission. A cardiologist blinded to the patient’s management analyzed the LV global longitudinal strain (GLS). The control group comprised normal subjects matched according to gender and age.
On day 1 median (25th–75th percentile) GLS was clearly impaired in SAH patients compared to controls [−16.7 (−18.7/−13.7) % versus −20 (−22/−19) %, p < 0.0001], whereas LVEF was preserved [65 (59−70) %]. GLS was severely impaired in patients with a WFNS score of V versus III–IV [−15.6 (−16.9/−12.3) % versus −17.8 (−20.6/−15.8) %, p = 0.008]. Seventeen (37 %) patients had a severe GLS alteration (>−16 %). In these patients, GLS improved from day 1 [−12.4 (−14.8/−10.9) %] to last evaluation [−16.2 (−19/−14.6) %, p = 0.0007] in agreement with the natural evolution of stress cardiomyopathy.
On the basis of LV GLS assessment, we demonstrated for the first time that myocardial alteration compatible with a stress cardiomyopathy is detectable in up to 37 % of patients with severe SAH while LVEF is preserved. GLS could be used for sensitive detection of stress cardiomyopathy. This is critical because cardiac impairment remains a major cause of morbidity and mortality after SAH.
KeywordsSpeckle tracking 2D strain Subarachnoid hemorrhage Stress cardiomyopathy Takotsubo
Aneurysmal subarachnoid hemorrhage (SAH) remains a life-threatening condition which occurs mainly in healthy individuals . Its mortality rate has not decreased over the past decade and reaches up to 30 % [1, 2]. Acute transient heart failure, or stress cardiomyopathy, has been widely described in the early phase of SAH [3, 4, 5] and remains a cause of prehospital death . Although its pathophysiology is not fully elucidated, it seems that ischemic phenomena are not involved and that sympathetic autonomous system hyperactivity could play a key role . Recent data confirm the link between stress cardiomyopathy and poor neurological outcome . However, classical left ventricle ejection fraction (LVEF) assessment with visual evaluation, the Simpson technique, or assessment of regional wall motion abnormalities bears substantial interobserver variability . Two-dimensional speckle tracking images, or 2D strain, with echocardiography allows one to track a natural myocardial marker within the myocardium (known as speckle) by standard transthoracic echocardiography (TTE). It provides unique insights into myocardial function such as tissue deformations and strain rate, which is the rate of deformation [10, 11]. Speckle tracking can capture longitudinal, circumferential, and radial strain , which are usually not fully assessed by echocardiography. Moreover, longitudinal strain bears very low interobserver variability  and provides objective data. This method is more sensitive than classical echographic LVEF evaluation because systolic function impairment could be missed with seemingly normal LVEF [12, 13, 14, 15]. In an experimental model of sepsis  or in pediatric sepsis , speckle tracking could detect early myocardial dysfunction despite preserved LVEF.
In this study, we aimed to evaluate whether speckle tracking could allow more subtle detection of cardiac systolic dysfunction as compared with the standard left ventricular (LV) systolic function assessed with 2D echocardiography in patients with severe SAH. A population of healthy subjects matched for gender and age was used as control.
We conducted an observational pilot study in one neurosurgical intensive care unit (ICU) (University Hospital of Nantes) from 1 January 2012 to 31 December 2013. The Ethics Committee of the University Hospital of Rennes approved the study (no. 12–44). Written information regarding the study was delivered to the patient’s next-of-kin and retrospectively to the patient whenever neurological recovery was deemed appropriate.
Consecutive adults (≥18 years) admitted with a severe SAH , defined as a World Federation of Neurological Surgeons (WFNS) grade ≥III, were eligible. Diagnosis of aneurysmal SAH was upheld after a brain computed tomography (CT) scan and brain arteriography. Consecutive patients admitted to our ICU for a severe SAH during the 2-year study period were eligible for inclusion.
Patients with a history of cardiac ischemic disease or heart surgery were not eligible. Patients who could not benefit from TTE within the first 24 h after ICU admission were not included. Patients with clinical signs of brain death  at the time of inclusion, with a post-traumatic SAH or a cerebral mycotic aneurysm were not eligible. Patients with a low acoustic window or poor-quality images on which to perform 2D speckle tracking were excluded.
SAH management 
A brain CT scan confirmed diagnosis of aneurysmal SAH. Aneurysm was further confirmed during an arteriography with an endovascular coiling procedure or a surgical clipping in the first 24 h after the patient’s admission. Ventriculostomy was performed by the attending neurosurgeon in case of hydrocephalus. Patients with a Glasgow Coma Score (GCS) ≤8 were sedated with a continuous intravenous infusion of fentanyl (2–5 μg kg−1 h−1) or sufentanil (0.2–0.5 μg kg−1 h−1) and midazolam (0.2–0.5 mg kg−1 h−1) and were mechanically ventilated . Cerebral perfusion pressure was maintained at ≥60 mmHg with norepinephrine . Intracranial hypertension was defined as an intracranial pressure (ICP) ≥25 mmHg and treated with a bolus of mannitol (0.5 g kg−1) . If ICP remained elevated after osmotherapy, barbiturates were administered (sodium thiopental) with an intravenous bolus of 2–3 mg kg−1 followed by a continuous infusion of 2–3 mg kg−1 h−1 . Sedation was stopped when patients were considered at low risk of intracranial hypertension. Nimodipine was intravenously administered on admission to the ICU (1–2 mg h−1) and delivered via the enteral feeding tube as soon as enteral nutrition was delivered. Diagnosis of vasospasm was screened with transcranial Doppler twice a day and diagnosis was upheld during arteriography by a trained neuroradiologist . Cardiovascular management was left to the attending physician’s discretion depending on classical echographic parameters (LVEF, preload dependency parameters), pulse pressure variations, and central pulse pressure (CPP) .
TTE was performed with a Vivid S6® (General Electrics) equipped with a 2.5-MHz transducer. All echocardiographic off-line analyses were performed by a single cardiologist expert in speckle tracking analysis (N.P.) on an EchoPac® (General Electrics). The cardiologist was blinded to the patient’s management and outcome.
TTE was performed within the first 24 h after the patient’s ICU admission (day 1) and on day 3 and day 7 after ICU admission. One anesthetist with board-certified echocardiographic training and daily practice (R.C.) and one cardiologist (M.L.) performed the TTEs. The following echocardiographic loops were recorded over three cardiac cycle with a high frame rate (>70 s−1): left parasternal long and short axis views, apical two-, three-, four-, and five-chamber views. A recording of tissue Doppler imaging (TDI) of the lateral and septal part of the mitral annulus was performed. Mitral inflow Doppler measurements included early (E) and late (A) peak diastolic velocities and the E/A ratio. Using the five-chamber view, we measured the velocity time integral (VTI) at the level of the left ventricular outflow track.
In order to analyze the right ventricle (RV) a recording of the tricuspid annular plane systolic excursion (TAPSE) was performed. A qualitative examination of potential valvular pathologies was finally performed with a color Doppler analysis.
Off-line and strain analysis
The LV thickness and the end-diastolic LV diameter were measured with the time-motion mode in the left parasternal long axis view. The LV ejection fraction (LVEF) was evaluated with the Simpson calculation in the four-chamber and two-chamber views. The systolic S, diastolic E′, and A′ peak velocities were measured at the septal and lateral aspects of the mitral annulus as well as the E/E′ ratio at the lateral aspect of the mitral annulus.
The longitudinal strain was measured in the three-, four-, and two-chamber view allowing the calculation of global longitudinal strain (GLS) according to previously validated methods, by an expert cardiologist (N.P.) . Strain is a measure of myocardial muscle fiber shortening during contraction and is calculated as the systolic segment shortening between end-systolic (ES) segment length (L) and end-diastolic (ED) length: strain = (LES − LED)/LED × 100 %. Data are expressed negatively, implying a myocardial fiber shortening: the lower the strain value (i.e., the more negative the value), the greater the fiber shortening and contraction. Regional LV longitudinal strains were also analyzed at base, median, and apex segments. Since there were no data in the literature about speckle tracking in the ICU, we performed a pilot observational study. GLS was analyzed off-line after the patient’s discharge, in order to better describe stress cardiomyopathy in the setting of SAH.
Demographic data were recorded. Complications after SAH observed during ICU stay, such as vasospasm, episodes of epilepsy, intracranial hypertension, delayed ischemic deficits , cardiac failure, length of mechanical ventilation, ICU length of stay or in-ICU death were also recorded. An electrocardiogram was systematically performed on the patient’s arrival and anomalies were recorded. Blood samples were obtained on the patient’s arrival to measure high sensitivity troponin-T (Hs troponin-T) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Finally when collecting TTE measurements, we also recorded heart rate (HR), systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and ICP.
The primary aim of the study was to compare the GLS pattern of stress cardiomyopathy after SAH with LVEF values. Secondary aims were to evaluate the correlations between GLS, LVEF, NT-proBNP, Hs troponin-T. An exploratory analysis was performed on general ICU events or echocardiographic parameters (GLS included) to evaluate the risk factors for poor neurological outcome, 3 months after the onset of SAH. The neurological outcome was assessed with the modified Rankin scale (mRS) score, 3 months after the onset of SAH by phone call by one anesthetist (R.C.) [24, 25]. An mRS score of 1–3 was considered a good clinical outcome and a score of 4–6 was considered a poor outcome .
In order to verify that our findings were specific of SAH, we randomly matched two SAH patients for one healthy subject, according to age and gender. Healthy subjects were free of moderate to severe cardiac co-morbidities. They could be included in the presence of cardiovascular risk factors (chronic hypertension, hypercholesterolemia). This control group comprised healthy relatives from a family mitral valve prolapse-screening project (PHRC-I RC12-0143). Patients were in spontaneous ventilation, in steady hemodynamic state, and without any mitral valve abnormality.
Continuous data are expressed as mean (±standard deviation) or median (25th–75th percentile) accordingly. Categorical data are expressed as N (%). Parametric and non-parametric values were compared using the Student t test and Mann–Whitney test, respectively, or the Kruskal–Wallis test with Dunn’s test for intergroup comparison. Categorical values were compared with the Chi-square test or the Fisher test. Pearson’s r was used for assessing correlations between variables. Regarding the exploratory analysis of poor neurological outcome, exact logistic regression analysis, adapted to small sample size, was used to examine the effect of multiple risk factors (age, sex, Fisher grade, WFNS grade, interventional therapy, ICP hypertension, LVEF, and strain data) on neurological outcome. Since no data are available in the current literature regarding LV GLS assessment in adult patients undergoing mechanical ventilation, sample size calculation was not possible. We therefore performed a 2-year pilot study. Values were statistically significant with a p value less than 0.05. Statistical analyses were performed with GraphPad Prism® software and SAS® software (SAS 9.3, Institute, Cary, NC).
Baseline characteristics of the 46 patients
Overall population, N = 46
GLS ≤−16 %, N = 29 (63 %)
GLS >−16 %, N = 17 (37 %)
Distribution of cerebral aneurysms
Middle cerebral artery
Anterior communicating artery
Posterior cerebral arteries
Chronic medication before SAH
Echocardiographic and speckle tracking data
Cardiac and echocardiographic data in 46 patients on day 1 after ICU admission
Overall population, N = 46
GLS ≤−16 %, N = 29 (63 %)
GLS >−16 %, N = 17 (37 %)
Heart rate (beats min−1)
Mean blood pressure (mmHg)
Thiopental N (%)
Hs troponin-T (μg L−1)
NT pro-BNP (pg mL−1)
EKG events N (%)
Global longitudinal strain (%)
Mitral in-flow E wave (m s−1)
Mitral in-flow A wave (m s−1)
Mitral in-flow E/A ratio
Tissue Doppler imaging at the lateral corner of the mitral annulus
S wave (m s−1)
E′ (m s−1)
A′ (m s−1)
Tissue Doppler imaging at the septal corner of the mitral annulus
S wave (m s−1)
E′ (m s−1)
A′ (m s−1)
Lateral E/E′ ratio
Septal E/E′ ratio
A regional analysis of longitudinal strain was performed on day 1 in 704 segments out of 782 (Fig. 1). LV longitudinal regional strain values displayed a significant gradient between base [−13.5 (−16.6/−9.6) %], median [−15.9 (−17.9/−13.7) %], and apex segments [−20 (−23.6/−15.9) %] (p = 0.002 and p = 0.001, respectively). There were no association between the aneurysm location and GLS (p = 0.7).
Comparison with the control group
Twenty-six subjects were included. Seventeen control (65 %) patients were female and nine (35 %) were male. Three (11.5 %) subjects were treated for chronic hypertension (p = 0.1, compared to SAH patients). The median age of the control group was 54 (42–63) and did not differ compared to SAH patients (p = 0.5). LVEF was higher in the SAH group [65 (58–70) %] than in the control group [61 (58–65) %, p = 0.003]. However GLS was more impaired in the SAH group [−16.7 (−18.7/−13.7) %] than in the control group [−20 (−22/−19) %, p < 0.0001] (Fig. 2). There was a significant regional strain gradient between the base, median, and apex segments in the control cohort (p = 0.001 and p = 0.002, respectively).
Intra- and interobserver variability of GLS measurements
Five (11 %) patients were randomly assigned to assess variability. Interobserver variability was 8 % and intraobserver variability was 3 %.
Biomarkers and electrocardiographic findings on admission
On ICU admission median Hs troponin-T was 24 (11–143) μg L−1 and median NT-proBNP was 307 (182–952) pg mL−1 (Table 2). The EKG events recorded were paroxysmal atrial fibrillation and flutter in 4 (9 %) patients, premature ventricular beat in 3 (6 %), branch block in 4 (9 %), negative T waves in 7 (15 %), negative ST segment in 4 (9 %), and positive ST segment in 1 (2 %) patient. Seventeen (37 %) patients displayed at least one EKG event. Patients in the GLS >−16 % group displayed significantly more EKG events than in the group with GLS ≤−16 % (p = 0.02) (Table 2).
Exploratory analysis: in-ICU complications and outcomes
Thirteen patients died in the ICU (28 %). We found no association between norepinephrine infusion or thiopental administration, which could alter loading conditions, and GLS (Table 2). Three months after the SAH onset, 19 (41 %) patients had a favorable neurologic outcome (mRS 1–3) and 27 (59 %) had a poor neurologic outcome (mRS 4–6). In univariate analysis, factors associated with a poor neurologic outcome were a poor WFNS grade, episode of intracranial hypertension, and administration of thiopental. Neither GLS, LVEF, nor other echographic parameters such as systolic S wave or diastolic parameters were independently associated with the neurological outcome. In multivariate analysis, only intracranial hypertension remained as a risk factor associated with poor neurological outcome, with a very large interval of confidence [OR = 20.3 (3.8–153.9), p < 0.0001]. These data should therefore be interpreted with caution.
We describe for the first time myocardial longitudinal strain alterations in patients with severe SAH compared to controls. Up to 37 % of patients have severe GLS impairment, which improves promptly in agreement with the evolution of stress cardiomyopathy. Interestingly, longitudinal strain allows sensitive detection of systolic function impairment with preserved LVEF.
LV contraction during systole is a complex phenomenon . First, longitudinal myocardial fibers are contracted. Second, a circumferential contraction is observed leading to a rotation and twist movement of the LV. Finally, these movements lead to a radial LV thickening. In the setting of cardiomyopathy, several data demonstrate that GLS is altered with preserved LVEF aortic valve stenosis [12, 13], heart failure , and amyloidosis . The fact that we found preserved LVEF with altered GLS is in accordance with the diagnosis of stress cardiomyopathy. There is also growing evidence that systolic short-term alterations are associated with poor outcome after SAH . Strain could therefore be a valuable approach to enhance diagnosis and maybe cardiac management in the future.
There are currently very few data in the literature regarding LV strain values in patients under mechanical ventilation and the accurate threshold defining GLS impairment in the ICU remains unknown. In the cardiology literature, the cutoff defining impaired GLS is >−18 %: in a large nationwide cohort of 1266 patients without known heart diseases and diabetes , overall strain was −18.4 %. In another cohort of 250 patients , overall strain was −18.7 %. The lower limit of normal values is generally considered at the threshold of −16 %. When we started our study, no data were available about speckle tracking in the ICU. We developed a cohort matched with age, gender, and minor cardiac co-morbidities in order to “mimic” SAH patients. Although these patients were not under mechanical ventilation or receiving catecholamine treatments, which alter loading conditions , we used our cohort to compare GLS and regional gradients. To the best of our knowledge, only one study was published with general ICU patients . In this 20 ICU patient cohort under mechanical ventilation with various conditions , GLS was preserved (−18.3 %). All these elements strongly suggest that strain impairment described in the current results is specific of SAH, unlike strain regional gradient. Second, and importantly, there was a clear GLS improvement over time in the group of patients with severe GLS impairment (Fig. 3). This feature is highly suggestive of stress cardiomyopathy [30, 31, 32]. Altogether our data suggest a stress cardiomyopathy in up to 37 % of severe SAH patients and that speckle tracking analysis could be a sensitive tool to detect moderate systolic impairment when classical LVEF could be inaccurate in this setting. However, and until further data are available, LVEF is the best tool to trigger specific therapies in case of cardiogenic shock.
Other echographic parameters displayed anomalies. The mitral systolic S wave assessed by Doppler tissue imaging is decreased. This is congruent with the fact that there is an LV strain impairment of basal segments and other authors already pointed out LV basal dyskinesis . The major drawback of the S wave is that it provides systolic function data in a very narrow area, unlike strain which provides global LV data. There were significantly more relaxation alterations in patients with severe GLS impairment (Table 2), in natural accordance with systolic dysfunction. Nonetheless, filling pressures evaluated with the E/E′ ratio were comparable in both groups (Table 2) and patients with severe GLS impairment did not display more pulmonary edema.
Our study has several limitations. Although we excluded patients with major cardiac history, it is always possible that chronic heart failure was missed. However, in our cohort, no patient displayed echographic patterns compatible with a chronic heart failure such as segmental dyskinesis, dilated or hypertrophic cardiomyopathy, or valve dystrophy. Furthermore the increase of cardiac biomarkers and the GLS improvement over time are in accordance with the current definition of stress cardiomyopathy . We therefore strongly believe that we described stress cardiomyopathy features in the SAH setting without being misled by chronic asymptomatic heart failure. In the subgroup of patients with preserved GLS (≤−16 %), 9 (31 %) had a past history of chronic hypertension, which can per se induce GLS impairment . The diagnosis of stress cardiomyopathy in this subgroup is challenging with GLS. However recent data suggest that in well-treated patients with chronic hypertension, strain is not impaired compared to controls . Our choice of control group is also questionable because patients were not under mechanical ventilation. We cannot rule out that our findings in SAH patients are, at least in part, explained by mechanical ventilation. Also, some subjects in the control cohort were treated for chronic hypertension, which could impair GLS. These aspects could generate discrepancies between the groups. Finally, we cannot ascertain the absence of link between patient’s outcome or in-ICU events and strain alterations. Moreover, because of the small sample size of our population, the analysis of risk factors of poor neurological outcome should be interpreted with great caution.
Severe SAH patients display GLS impairment with prompt recovery, along with moderate elevation of cardiac biomarkers, suggesting that stress cardiomyopathy is present. GLS is impaired even in the context of preserved LVEF, which is congruent with previous data in various settings (aortic stenosis, amyloidosis). As this study is mainly observational, no definitive conclusion can be drawn regarding the consequences of GLS alterations on the patient’s outcome. Also, the present pilot observational study does not allow modification of the current management of SAH patients. However, considering the lack of clear guidelines of SAH-induced stress cardiomyopathy management, further studies could delineate the exact place of strain in the management of SAH in ICU.
This study was supported in part by a grant from the Clinical Research Hospital Program (PHRC) of the French Ministry of Health (PHRC-I RC12-0143 in 2012), and a grant from the Fédération Française de Cardiologie (no R11065NN–RAK11093NNA in 2012). T. le Tourneau was supported by INSERM (INSERM Translational Research Grant 2012–2016).
Compliance with ethical standards
Conflicts of interest
The authors have no conflict of interest to declare about this work.
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