Incremental prognostic value of global longitudinal strain to the coronary microvascular resistances in Takotsubo patients

doi:10.21203/rs.3.rs-1762366/v1

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Incremental prognostic value of global longitudinal strain to the coronary microvascular resistances in Takotsubo patients

https://doi.org/10.21203/rs.3.rs-1762366/v1

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Background: Global longitudinal strain (GLS) allows an accurate assessment of left ventricular function with prognostic value. We aimed to evaluate whether the assessment of GLS in the acute phase of Takotsubo syndrome (TTS) provides incremental prognostic value to the degree of impaired microvascular resistance (MR) in TTS patients at 1-year follow-up.

Methods: We recruited 78 consecutive patients admitted for TTS who underwent cardiac angiography and echocardiography from January 2017 to June 2021. Left anterior descending coronary artery non-hyperaemic angiography-derived index of microcirculatory resistance (LAD NH-IMRangio) was calculated. NT-proBNP, high-sensitive cardiac troponin T (hs-cTnT), left ventricular ejection fraction (LVEF) and GLS were measured at admission. Major adverse cardiac events (MACE) were defined as the composite of cardiovascular death, heart failure (HF) events, symptomatic arrythmias and acute myocardial infarctions.

Results: 67 patients had both GLS and NH-IMRangio available. Median age was 75.2 years and 88 % were women. Rate of MACE at 1-year was 23.9% mainly due to mild HF events. Kaplan-Meier curves showed higher rates of MACE at 1-year in patients with both higher LAD NH-IMRangio and GLS values compared with those with higher LAD NH-IMRangio and lower GLS values (60.0% vs 22.2%; p=0.0373). NT-proBNP levels at admission and the recovery of LVEF were correlated with GLS values while MR and hs-cTnT were not.

Conclusions: GLS provides incremental prognostic value to the degree of impaired MR in TTS patients. The combination of a poorer GLS with a higher degree of impaired MR was associated with a higher rate of MACE in these patients.

Global longitudinal strain

Coronary microvascular dysfunction

Microvascular resistance

Takotsubo cardiomyopathy

Index of microcirculatory resistance

Takotsubo syndrome (TTS) is an acute and transient cardiomyopathy that primarily affects postmenopausal women. The presence of left ventricular wall motion abnormalities in absence of obstructive epicardial coronary artery disease has been associated with an impaired microvascular function due to catecholaminergic toxicity (1–3). Recently, we have reported the prognostic value of an impaired microvascular resistance (MR) in TTS patients using non-hyperaemic angiography-derived index of microcirculatory resistance (NH-IMRangio)(4), a novel technique to assess coronary microvascular dysfunction (CMD) (5–8).

Left ventricular ejection fraction (LVEF) has also been related with prognosis in TTS patients (9). Global longitudinal strain (GLS) has been consolidated as a non-invasive and more sensitive technique with greater prognostic discrimination than LVEF to assess systolic function (10). GLS by two-dimensional speckle tracking echocardiography is based on tracking the movement of stable acoustic patterns within the myocardium frame-by-frame throughout the cardiac cycle (11) and it has shown a significant role in predicting cardiovascular outcomes in patients with cardiac diseases (12,13). Moreover, GLS has also been useful to assess the recovery of myocardial abnormalities in patients with TTS (14–16). However, its prognostic value in TTS patients has not been fully elucidated (17,18).

In this study, we aimed to investigate whether the assessment of GLS in the acute phase of TTS provides incremental prognostic value to the degree of impaired MR in TTS patients. In addition, we also evaluated its correlation with cardiac biomarkers such as NT-proBNP and high sensitive-cardiac troponin T (hs-cTnT).

Study population

We conducted a retrospective, observational, single-center study which recruited all consecutive patients admitted for TTS from January 2017 to June 2020 in a tertiary center in Barcelona (Spain). All inclusion criteria had to be met: a) ≥ 18 years of age, b) diagnosis of TTS according to modified Mayo Clinic criteria (19), c) performance of an echocardiogram performed within the first 6 hours after admission to the emergency room and a coronary angiography (CAG) in the first 24 hours of the onset of the symptoms, and d) signed informed consent. We excluded those patients who presented: a) history of coronary artery bypass grafting, b) newly diagnosed coronary artery disease in the same territory of the regional wall motion abnormality, and c) patients in atrial fibrillation.

The study was performed in accordance with the standards set by the “Declaration of Helsinki” and was approved by the Clinical Research Ethics Committee.

Study variables

Patient’s demographics, cardiovascular risk factors, and electronical clinical history were collected from medical reports at admission and discharge. Analytical parameters were registered from the first blood test or arterial blood gas samples at admission. NT-proBNP and high-sensitivity cardiac troponin-T (hs-cTnT) were measured by electrochemiluminescence immunoassays on a Cobas e601 platform (Roche Diagnostics, Switzerland). NT-proBNP range was 5–35.000 pg/ml with a coefficient of variation (CV) ≤ 3.5%, whereas the hs-cTnT range was and 3–10.000 ng/L with a CV ≤ 4.0%. The Modification of Diet in Renal Disease Study equation (MDRD) (20) was used to calculate the estimated glomerular function rate (eGFR). We calculated the LVEF by echocardiography using the biplane Simpson method. Treatments and/or procedures performed during hospital stay were also registered.

Global longitudinal strain calculation

Echocardiographic images were obtained using commercially available CX50 or Sparq-DS echocardiographic systems (Koninklijke Philips Electronics N.V. 2019) equipped with a S5-1 (Purewave) 1–5 MHz sectorial cardiac transducer. Echocardiography was performed according to European Association of Cardiovascular Imaging recommendations (21). Echocardiographic data were digitally recorded in cine loop format and 2D strain analysis were performed offline using 2D strain imaging software (QLAB Advanced Quantification Software 13.0, Koninklijke Philips Electronics N.V. 2019) by one investigator who was blinded to the clinical data. Software automatically traced the endocardial borders at the end of the systole with further manual adjustments if necessary to optimize automated speckle tracking. An 18-segment model was presented and average GLS was calculated as the mean of all segments. Moreover, LV was divided into three slices to calculate basal, mid-ventricular and apical longitudinal strain (LS) as the average value of six segments of each one. GLS and LS presented negative values due to the ventricular shortening during systole.

3D-QCA, QFR and NH-IMRangio calculation

We analyzed the state of the coronary microcirculation by assessing the left anterior descending coronary artery (LAD) NH-IMRangio value. Two certified readers performed the 3D-QCA analysis and the QFR computation in the CoreLab of the MedStar Washington Hospital Center using the QAngio XA 3D software package (Medis Suite 3.2.48.8, Medis, Leiden, Netherland). A proximal and a distal point were established in two angiographic projections > 25º apart. The software automatically reconstructed a 3D model of the LAD without its side branches and performed the 3D-QCA analysis and the QFR computation. Mean aortic pressure during CAG and TIMI frame count were also recorded for the calculation of the LAD NH-IMRangio according to the formula used in the validation studies (5,7).

$$NH-IMRangio=Mean aortic pressure \left(rest\right)*QFR \left(rest\right)*\left(\frac{Nframes \left(rest\right)}{frame adquision rate}\right)$$

Impaired MR was defined as a value of LAD NH-IMRangio ≥ 25. Although there is no established specific cut-off point to define an impaired MR in TTS patients, we consider that the widely spread cut-off point of 25 could be suitable for this population (22).

Follow-up and outcomes

The primary endpoint of this study was the rate of major adverse cardiac events (MACE) at 1-year follow-up. MACE were defined as a composite endpoint of cardiovascular death, HF events (23), symptomatic arrhythmias and acute myocardial infarctions (AMI). Cardiovascular death was defined as any death secondary to AMI, HF, sudden cardiac death, stroke, cardiovascular procedure, cardiovascular hemorrhage or other cardiovascular causes. AMI was defined according to the fourth definition of AMI (24). HF events included any emergency department visit or hospitalization for HF as well as any urgent or unscheduled outpatient office visits with a primary diagnosis of HF, where the patient exhibited new or worsening symptoms of HF on presentation and received initiation or intensification of treatment specifically for HF that occurred from the first month after hospital discharge (25). The follow-up was carried out by reviewing clinical courses and medical reports included in the national health network. The adjudication of MACE was performed by the study investigators. All patients completed the 1-year follow-up period.

A follow-up echocardiogram was performed between the third and sixth month after hospital discharge. To assess the recovery of LVEF the delta LVEF was calculated. Delta LVEF was defined as the difference between LVEF on follow-up echocardiogram and LVEF on admission echocardiogram.

Secondary endpoints were: a) to study the relationship between CMD and GLS in TTS patients, b) to investigate the correlation between GLS and cardiac biomarkers at admission (NT-proBNP and hs-cTnT).

Statistical analysis

Results are presented as the mean (standard deviation) for continuous variables with a normal distribution, median (interquartile range) for continuous variables with a non-Gaussian distribution, and with counts and percentages in case of categorical variables. We divided our cohort in 4 groups according to GLS and NH-IMRangio median values (≥-11.24% and ≥ 40.94, respectively). We used the x² test or Fisher exact test for comparing categorical variables. For continuous variables, they were analyzed by t-test or ANOVA in the case of a normal distribution and by Mann-Whitney U-test or Kruskall-Wallis test in the case of a non-normal distribution.

Correlations were analyzed using Pearson if variables presented a gaussian distribution or Spearman if they presented a non-gaussian distribution.

We performed Kaplan-Meier survival curves to compare 1-year MACE rates in groups divided as a function of the median value of GLS and NH-IMRangio, using the long-rank test to compare the rates of MACE.

Significance level was set at p < 0.05. All statistical analyses were performed using Stata 13.0 for Windows.

Baseline characteristics

We registered 78 patients with TTS during the study period. We calculated both the GLS and the LAD NH-IMRangio in 67 of them (Fig. 1). No significant differences were found between patients without GLS and / or LAD NH-IMRangio available (Table S1 in supplemental material). Almost 90% of the patients were women with a median age of 75.2 years. The classical pattern with apical involvement was the most prevalent wall motion abnormality while secondary forms of TTS were around 35%. More than 45% of the patients were admitted with signs of HF and 20% of our cohort needed some kind of mechanical ventilation. Fifty-eight patients (86.6%) showed a LAD NH-IMRangio value ≥ 25.

Sixty patients (89.6%) presented an abnormal value of GLS (>-18%). Concerning the three LV slices, apical LS values were worse than basal and mid-ventricular LS values (-9.3% vs -12.9% and − 10.9%, respectively; p = 0.008).

Baseline characteristics of the study population according to median values of LAD NH-IMRangio and GLS are detailed in Table 1.

Table 1

Baseline characteristics of the study population according to GLS and NH-IMRangio values.
	All patients (n = 67)	GLS ≤ -11.24 & LAD NH-IMRangio ≤ 40.94 (n = 15)	GLS > -11.24 & LAD NH-IMRangio ≤ 40.94 (n = 19)	GLS ≤ -11.24 & LAD NH-IMRangio > 40.94 (n = 18)	GLS >-11.24% & LAD NH-IMRangio > 40.94 (n = 15)	p
PATIENT-RELATED FACTORS
Age (years)	75.2 (67.5–81.0)	76.7 (60.3–80.7)	79.5 (70.4–83.3)	70.6 (64.3–73.6)	78.6 (70.1–86.0)	0.020
Male gender, %	11.9 (8)	0 (0)	15.8 (3)	22.2 (4)	6.7 (2)	0.212
Hypertension, %	71.6 (48)	73.3 (11)	84.2 (16)	55.6 (10)	73.3 (11)	0.282
Diabetes mellitus, %	22.4 (15)	33.3 (5)	31.6 (6)	11.1 (2)	13.3 (2)	0.263
Dyslipidemia, %	53.7 (36)	60 (9)	57.9 (11)	55.6 (10)	40.0 (6)	0.675
Current smoker, %	9.0 (6)	6.7 (1)	5.3 (1)	16.7 (3)	6.7 (1)	0.610
Previous coronary artery disease, %	7.5 (5)	13.3 (2)	10.5 (2)	5.6 (1)	0.0 (0)	0.510
Chronic kidney disease, %	11.9 (8)	6.7 (1)	21.1 (4)	11.1 (2)	6.7 (1)	0.511
Previous malignancies	17.9 (12)	13.3 (2)	15.8 (3)	27.8 (5)	13.3 (2)	0.642
Previous psychiatric disorder, %	34.3 (23)	26.7 (4)	36.8 (7)	33.3 (6)	40.0 (6)	0.881
TAKOTSUBO-RELATED FACTORS
Secondary forms of TTS, %	35.8 (24)	33.3 (5)	36.8 (7)	22.2 (4)	53.3 (9)	0.321
Clinical presentation:, %
- Chest pain	65.7 (44)	53.3 (8)	52.6 (10)	88.9 (16)	66.7 (10)	0.080
- Vegetative symptoms	49.3 (33)	80.0 (12)	42.1 (8)	50.0 (9)	26.7 (4)	0.028
- Dyspnea	52.2 (35)	46.7 (7)	63.2 (12)	22.2 (4)	80.0 (12)	0.007
- Palpitations	3.0 (2)	6.7 (1)	5.3 (1)	0.0 (0)	0.0 (0)	0.560
- Syncope	4.5 (3)	6.7 (1)	0.0 (0)	5.6 (1)	6.7 (1)	0.735
- Cardiac arrest	6.0 (4)	6.7 (1)	5.3 (1)	11.1 (2)	0.0 (0)	0.608
Previous stressful situation, %	61.2 (41)	53.3 (8)	57.9 (11)	55.6 (10)	80.0 (12)	0.399
Patterns of TTS:, %
- Classic (apical)	73.1 (49)	80.0 (12)	79.0 (15)	66.7 (12)	66.7 (10)	0.708
- Mid-ventricular	14.9 (10)	6.7 (1)	15.8 (3)	22.2 (4)	13.3 (2)	0.659
- Inverted (basal)	7.5 (5)	0.0 (0)	5.3 (1)	5.6 (1)	20.0 (3)	0.183
- Atypical	4.5 (3)	13.3 (2)	0.0 (0)	5.6 (1)	0.0 (0)	0.222
GLS average, %	-11.24 (-16.02 / -8.3)	-14.1 (-18.5 / -13.1)	-8.7 (--9.6 / -6.5)	-16.4 (-17.4 / -14.9)	-8.1 (-10.6 / -6.6)	< 0.001
SBP (mmHg), %	126 (113–147)	125 (97–143)	140 (120–180)	128 (116–142)	117 (102–128)	0.208
Heart rate (bpm), %	85 (75–99)	77 (62–87)	90 (77–117)	81 (76–91)	90 (78–104)	0.004
Left ventricular ejection fraction at admission, %	44 (39–52)	53 (43–62)	42 (39–56)	42.5 (38–48)	43 (37–48)	0.061
BASELINE ECG-RELATED FACTORS
ST-segment elevation:, %	50.8 (34)	46.7 (7)	52.6 (10)	44.4 (8)	60.0 (9)	0.819
Long QT interval, %	44.8 (30)	53.3 (8)	42.1 (8)	55.6 (10)	26.7 (4)	0.343
- QT interval (msec)	44 (430–499)	473 (420–526)	446 (435–500)	446.5 (430–493)	437 (416–494)	0.623
BLOOD TEST / ARTERIAL BLOOD GAS AT ADMISSION
pH	7.36 (7.29–7.44)	7.36 (7.34–7.38)	7.39 (7.25–7.44)	7.44 (7.36–7.52)	7.33 (7.28–7.38)	0.714
Lactate (mmol/L)	2.0 (0.9–3.1)	3.0 (2.0-7.1)	1.6 (0.9-3.0)	1.75 (0.9–2.6)	2.1 (0.8–3.4)	0.720
Hemoglobin (g/L)	127 (115–137)	121 (115–133)	125 (112–140)	131 (127–140)	122 (107–137)	0.096
hs-TnT (ng/L)	350 (156–777)	363 (173–862)	356 (73–630)	253 (122–489)	496 (210–966)	0.575
eGFR (ml/min/1.73m²)	71.4 (50.9–85.6)	73.7 (40.9–90.4)	59.2 (41.3–83.7)	77.0-73.6-85.6)	68.5 (54.3–83.5)	0.273
NT-proBNP (pg/ml)	3664 (1924–8144)	2697.5 (1321–5003)	2971 (897–5160)	4052.5 (2265.5-8824.59	6955 (3664–10445)	0.030
LAD NH-IMRangio	40.9 (27.8–61.3)	28.3 (18.7–33.6)	27.9 (21.8–36.1)	64.3 (57.3–86.9)	56.5 (46.2–66.4)	< 0.001
THERAPEUTIC MANAGEMENT
Need of non-invasive ventilation, %	17.9 (12)	20.0 (3)	21.1 (4)	11.1 (2)	20.0 (3)	0.854
Need of invasive ventilation, %	13.4 (9)	13.3 (2)	10.5 (2)	11.1 (2)	20.0 (3)	0.855
Use of inotropes, %	17.9 (12)	13.3 (2)	15.8 (3)	11.1 (2)	33.3 (5)	0.353
Renal replacement therapy, %	4.5 (3)	6.7 (1)	0.0 (0)	0.0 (0)	13.3 (2)	0.199
Continuous variables are expressed as median (IQR) and categorical data as %.
kg/m2: kilograms per meter squared; TTS: Takotsubo syndrome; CAD: Coronary artery disease; GLS: global longitudinal strain; SBP: systolic blood pressure; bpm: beats per minute; msec: milliseconds; mmol/L: millimoles per liter; g/L: grams per liter; hs-TnT: high-sensitive Troponin T; ng/L: nanograms per liter; eGFR: estimated glomerular filtration rate; ml/min/1.73m2: milliliters per minute per 1.73 meter squared; pg/ml: picograms per milliliter; NH-IMRangio: non-hyperaemic angiography-derived index of microcirculatory resistance; LAD: left anterior descending artery; IQR: interquartile range.

Outcomes at 1-year follow-up based on GLS and NH-IMRangio values

Rate of MACE at 1-year follow-up was 23.9% (16 events), mainly due to HF events (12 events) which were mostly mild. Cardiovascular mortality was 3% (2 patients, one died of HF and the other had a sudden cardiac death). Only one patient presented an AMI during follow-up (non-ST elevation AMI). All-cause mortality at 1-year follow-up was 4.5% (3 patients). The detailed distribution of MACE among the 4 groups created according to GLS and LAD NH-IMRangio median values was shown in Table 2. Patients with both LAD NH-IMRangio and GLS values above the median population values (40.94 and − 11.24%, respectively) had a higher percentage of MACE at 1-year of follow-up, while patients with lower GLS and LAD NH-IMRangio values (both below the median) showed the lowest rate of MACE (p = 0.002) (Fig. 2). No differences were found in follow-up LVEF or delta LVEF between the groups.

Table 2

Outcomes at 1-year-follow-up based on GLS and NH-IMRangio median values
	All patients (n = 67)	GLS ≤ -11.24% and NH-IMRangio ≤ 40.94 (n = 15)	GLS > -11.24% and NH-MRangio ≤ 40.94 (n = 19)	GLS ≤ -11.24% and NH-IMRangio > 40.94 (n = 18)	GLS > -11.24% and NH-IMRangio > 40.94 (n = 15)	p-value
MACE at 1-year follow-up	23.9 (16)	6.7 (1)	10.5 (2)	22.2 (4)	60.0 (9)	0.002
In-hospital:, % (n)
- - All-cause death	1.5 (1)	0.0(0)	0.0 (0)	5.6 (1)	0.0 (0)	0.430
- - Cardiovascular death	1.5 (1)	0.0(0)	0.0 (0)	5.6 (1)	0.0 (0)	0.430
1-year follow-up:, % (n)
- - All-cause death	4.5 (3)	0.0 (0)	0.0 (0)	11.1 (2)	6.7 (1)	0.306
- - Cardiovascular death	3.0 (2)	0.0(0)	0.0 (0)	5.6 (1)	6.7 (1)	0.540
- Heart failure event	17.9 (12)	6.7 (1)	10.5 (2)	22.2 (4)	33.3 (5)	0.199
- Symptomatic arrhythmias	3.0 (2)	0.0 (0)	0.0 (0)	0.0 (0)	13.3 (2)	0.067
- Acute coronary syndrome	1.5 (1)	0.0 (0)	0.0 (0)	0.0 (0)	6.7 (1)	0.318
LVEF on follow-up echocardiogram	61 (56–66)	61 (57–65)	60 (56–68)	61 (50.5–66.5)	62 (55–66)	0.959
LVEF < 55% on follow-up echocardiogram, %	16.4 (11)	6.7 (1)	10.5 (2)	27.8 (5)	20.0 (3)	0.340
Delta LVEF, %	15 (9–20)	15 (7–23)	14.5 (7.5–19)	17 (14–23)	15 (6–16)	0.485
Continuous variables are expressed as median (IQR) and categorical data as % (n).
NH-IMRangio: non-hyperemic angiography-derived index of microcirculatory resistance; MACE: major adverse cardiovascular events; LVEF: left ventricle ejection fraction.

Prognostic value of GLS and LAD NH-IMRangio

Patients who developed MACE during the 1-year follow-up presented a worse LVEF at admission and also on the follow-up echocardiogram. Moreover, they showed both higher NT-proBNP and LAD NH-IMRangio values. GLS values did not differ between groups (Table 3).

Table 3

Predictors of major adverse cardiovascular outcomes. Univariate analysis (n = 67 patients)
Characteristic	No MACE (n = 51)	MACE (n = 16)	p-value
Age (years)	74.8 (70.1–80.7)	76.1 (64.8–85.1)	0.872
Male gender, %	11.8 (6)	12.5 (2)	0.937
Hypertension, %	70.6 (36)	75.0 (12)	0.733
Diabetes mellitus, %	23.5 (12)	18.8 (3)	0.689
Dyslipidemia, %	56.9 (29)	43.8 (7)	0.359
Current smoker, %	7.8 (4)	12.5 (2)	0.569
Chronic kidney disease, %	13.7 (7)	6.3 (1)	0.421
Previous coronary artery disease, %	7.8 (4)	6.3 (1)	0.832
Previous malignancies, %	21.5 (11)	6.25 (1)	0.186
Physical stressor, %	43.1 (22)	43.8 (7)	0.966
Secondary TTS forms, %	35.3 (18)	37.5(6)	0.872
Classical TTS pattern (apical)	72.6 (37)	75.0 (12)	0.847
Killip-Kimball > 1 at admission, %	43.1 (22)	56.3 (9)	0.359
ED-LV pressure (mmHg)	18 (14–23)	15 (12-25.5)	0.784
LVEF on admission (%)	45 (41–58)	40 (35–44)	0.010
Hemoglobin (g/L)	127 (115–137)	127 (112.5-138.5)	0.900
eGFR (ml/min/1.73m²)	71.4 (49.9–85.9)	71.90 (54.7–84.2)	0.803
NT-proBNP (pg/ml)	2895 (1581–5160)	10173.5 (5996.5-14035)	<0.001
hs-cTnT (ng/L)	350 (173–791)	346 (59.5–681)	0.602
NH-IMRangio LAD	36.1 (27.0-54.3)	63.8 (45.8–77.3)	< 0.001
GLS, %	-12.7 (-15.7 / -8.7)	-10.8 (-17.3 / -7.7)	0.607
Continuous variables are expressed as median (IQR) and categorical data as %.
MACE: Major adverse cardiac events; HR: hazard ratio; CI: confidence interval; TTS: Takotsubo syndrome; SBP: systolic blood pressure; mmHg: milimeters of mercury; ED-LV pressure: end-diastolic left ventricular pressure; LVEF: Left ventricle ejection fraction; g/L: grams per litre; eGFR: estimated glomerular filtration rate; ml/min/1.73m²: millilitres per minute/1.73 square metres; pg/ml: picograms per mililiter; hs-cTnT: high-sensitive cardiac troponin T; ng/L: nanograms per liter; NH-IMRangio LAD: non-hyperaemic angiography-derived index of microcirculatory resistance of left anterior descending coronary artery.

Kaplan-Meier analysis showed that patients with higher (i.e. poorer result) GLS and LAD NH-IMRangio values presented a higher rate of MACE at 1-year follow-up compared to patients with only LAD NH-IMRangio values above the median population value (p = 0.0373, log rank test). Detailed Kaplan Meier survival curves results were shown in Fig. 3.

Correlations between GLS with biomarkers, delta LVEF, and LAD NH-IMRangio

The GLS values presented a moderate positive correlation with NT-proBNP levels at admission (rho: 0.59; p < 0.001) and we also found a trend to a mild positive correlation between GLS with hs-cTnT (rho: 0.23; p = 0.063). On the other hand, a moderate negative correlation was found between GLS values and delta LVEF (rho: -0.40; p = 0.022) while there was a trend to a mild negative correlation between values of GLS and LAD NH-IMRangio values in TTS patients (rho: -0.21; p = 0.0829) (Fig. 4).

As far as we know, this is the first study that investigates the prognostic value and the relationship between GLS and microvascular resistances in TTS patients. The main findings of our study were: 1) the presence of a more impaired coronary microvascular resistance (MR) together with a worse GLS were associated with a higher rate of MACE at 1-year of follow-up, 2) LS was globally impaired in patients with TTS with worse values in apical segments, and 3) NT-proBNP at admission and the recovery of LVEF, but not MR and hs-cTnT, were correlated with GLS values.

First, a reduced LVEF on admission has been shown to have prognostic implications in patients with TTS (9,26,27). Assessment of the myocardial function of the left ventricle using GLS is a more accurate evaluation of the recovery of the myocardial abnormalities in these patients. Alashi et al (18) reported that GLS could have prognostic value incremental to LVEF in the long-term prognosis in TTS patients, while Dias et al (17) showed the prognostic value of GLS for in-hospital mortality in these patients. In our study, we found that patients who had simultaneously NH-IMRangio and GLS values above the median population values developed a higher rate of MACE during the 1-year follow-up than those with one or both values below the median value. Thus, in our cohort GLS provides incremental prognostic value to the degree of impaired MR in TTS patients.

As we have commented in the introduction, myocardial dysfunction in TTS could be not only secondary to catecholaminergic toxicity and CMD but also a "protective mechanism" to avoid further damage by the catecholaminergic surge. It has been hypothesized that in the myocardium, the switch from β2-adrenergic receptor Gs coupling to β2-adrenergic receptor Gi coupling in response to the catecholamine surge could limit the induction of apoptotic pathways but causing a negative inotropic effect (28,29). Interestingly, we found a trend towards a mild negative correlation between LAD NH-IMRangio and GLS that would support the hypothesis that part of the ventricular dysfunction in TTS patients could be a mechanism to minimize myocardial damage during the acute phase of the disease. Nevertheless, these data are only hypothesis generating and would require a multicenter, prospective validation.

Furthermore, we found an alteration of the LS longitudinal strain in the three LV slices (basal, mid ventricular and apical) with the apical region showing the worst LS values. Our results are aligned with previous studies that reported a global LV involvement despite the visual appearance of basal hypercontractility in TTS patients, being the apical GLS the most severely affected (30–32).

Finally, in our study, NT-proBNP levels at admission were positively correlated with GLS values while we found a trend to a mild positive correlation between hs-cTnT levels and GLS values. The release of NT-proBNP is associated with the degree of LV wall stress while hs-cTnT is a marker of myocardial injury. Thus, a worse myocardial contractility during the acute phase of TTS would favor a higher release of both cardiac biomarkers (33–35). On the other hand, although we did not find a significant correlation between NH-IMRangio and GLS values, we observed a trend towards worse GLS values in those patients with less impaired MR, suggesting that ventricular dysfunction in TTS patients may not be only due to myocardial damage. However, as mentioned, these data are of hypothesis-generating value at this stage.

The main limitation of our study is the small number of patients from a single center. However, to our knowledge, this is the first study analyzing the incremental prognostic value of GLS to the degree of impaired MR in TTS patients. Secondly, in patients who were not referred directly to the cath lab (STEMI code protocol), echocardiography was not performed at the same time as the CAG, so this would carry a bias for the correlation of both measurements. In addition, echocardiography was performed using a portable ultrasound machine in the cath lab or in the emergency room, which could lead to a poorer image quality and, in turn, a possible bias in GLS analysis. Nevertheless, we believe that performing bedside echocardiography reflects standard clinical practice and will facilitate its reproducibility by other groups in the future which in turn will facilitate external validation of our results.

GLS provided an incremental prognostic value to the degree of impaired MR in TTS patients. GLS is globally impaired in these patients with the apical segments being the most affected. NT-proBNP but not MR were associated with the GLS value in TTS patients. Future studies will be needed to validate these results and to fully understand the etiopathogenesis of ventricular dysfunction in TTS patients.

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No competing interests reported.

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Incremental prognostic value of global longitudinal strain to the coronary microvascular resistances in Takotsubo patients

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Abstract

Figures

Introduction

Methods

Study population

Study variables

Global longitudinal strain calculation

3D-QCA, QFR and NH-IMRangio calculation

Follow-up and outcomes

Statistical analysis

Results

Baseline characteristics

Outcomes at 1-year follow-up based on GLS and NH-IMRangio values

Prognostic value of GLS and LAD NH-IMRangio

Correlations between GLS with biomarkers, delta LVEF, and LAD NH-IMRangio

Discussion

Limitations

Conclusions

References

Additional Declarations

Supplementary Files

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