Takotsubo cardiomyopathy (TC) is characterized by transient hypokinesis of the left ventricular apex or midventricular segments with coronary arteries without significant stenosis. It is often associated with emotional or physical stress; however, its pathophysiology is still unclear. In the present study, we analyzed the alterations in blood viscosity and markers of endothelial damage induced by sympathetic stimulation in patients with previous TC. Seventeen women (mean age 71 years) with previous TC, included and investigated in the TC Tuscany Registry, were compared to a control group of 8 age- and risk factor-matched women with chest pain and coronary arteries free of stenosis. All subjects underwent the cold pressor test (CPT). Before and after the CPT, the hemorheologic parameters (whole blood viscosity at 0.512 s −1 and 94.5 s −1 , plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation), catecholamines, plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor levels were assessed. The patients with TC had significantly greater baseline PAI-1 levels (p <0.01) and lower erythrocyte deformability index values (p <0.01). After CPT, both the patients with TC and the controls had a significant increase in several hemorheologic parameters, catecholamines, and von Willebrand factor levels and a decrease in erythrocyte deformability index. However, the PAI-1 levels were significantly increased only in the patients with TC. Compared to the controls, the patients with TC had significantly greater values of whole blood viscosity at 94.5 s −1 (p <0.05), PAI-1 (p <0.01), von Willebrand factor (p <0.05) and lower erythrocyte deformability index values (p <0.01) after CPT. In conclusion, the results of the present study suggest that in patients with TC, the alterations in erythrocyte membranes and endothelial integrity induced by catecholaminergic storm could determine microvascular hypoperfusion, possibly favoring the occurrence of left ventricular ballooning.
The underlying pathophysiology of takotsubo cardiomyopathy (TC) remains unclear ; however, several mechanisms have been proposed, including multivessel epicardial spasm, acute microvascular dysfunction, catecholamine-induced myocardial stunning, transient obstruction of the left ventricular outflow tract, or aborted myocardial infarction due to transient thrombotic left anterior descending artery occlusion. Blood viscosity is known to increase during acute mental and physical stress owing to the catecholaminergic effect, resulting in a reduction in plasma volume with parallel increase in the hematocrit, resulting in hemoconcentration. However, the role of the blood components in favoring the occurrence of this syndrome has not yet been evaluated. In a cohort of previously investigated patients with TC, who were included in the Tuscany Registry, and a control group of women with chest pain and coronary arteries free of critical stenosis, we evaluated the changes in several hemorheologic variables and endothelial markers of vascular dysfunction before and after sympathetic stimulation using the cold pressor test (CPT).
Methods
In the Department of Heart and Vessels, from January to December 2007, 17 patients (all women, aged 71 ± 12 years) with previous TC diagnosed according to the Mayo Clinic criteria, as previously reported, were included in the Tuscany Registry of TC and previously investigated. A stressful situation resulted in precipitating the event in 13 patients with TC, whose symptoms had been chest pain or dyspnea. ST-segment elevation in V 1 to V 3 leads followed by T-wave inversion was the most frequent finding on the electrocardiogram at presentation. On the angiogram, the epicardial coronary vessels were free of critical lesions, and no coronary spasm or myocardial bridge was documented. The typical apical ballooning was documented with both angiography and echocardiography and had completely reverted in all patients with TC at follow-up.
For the control group, we recruited 8 age- and risk factor-matched women (mean age 67 ± 8 years) who had been admitted to our emergency department for acute chest pain, with angiographic demonstration of epicardial coronary arteries without critical stenosis. By study design, the eligibility criteria of the controls included normal left ventricular wall motion, normal electrocardiographic findings, and no troponin I increase at the index hospitalization.
Both patients and controls underwent CPT. The CPT is a standardized technique during which patients undergo sympathetic stimulation through right hand immersion in ice water for 180 to 220 seconds, as previously reported. Before and after CPT, several hemorheologic parameters, catecholamines, and the plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) plasma levels were assessed.
Venous blood samples were obtained by puncture of the antecubital vein with minimal stasis. To assess the hemorheologic profile, 20 ml of blood were anticoagulated with ethylenediaminetetraacetic acid according to the recommendations of the International Committee for Standardization in Hematology. The hemorheologic studies were performed by assessing whole blood viscosity (WBV), plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation. The WBV and plasma viscosity were measured at 37°C using the Rotational Viscometer (cup and bob type), Low Shear 30 (Contraves, Zürich, Switzerland). WBV was analyzed at shear rates of 0.512 s −1 and 94.5 s −1 . The plasma viscosity test was performed at a 94.5 s −1 shear rate. Erythrocyte deformability was assessed with a microcomputer-assisted filtrometer model MF4 (Myrenne GmbH, Roetgen, Germany) and estimated by a curve indicating erythrocyte filtration through a 10-minute recording to determine the rheologic properties of the erythrocytes, passing them through polycarbonate filters with 5-μm micropores. The initial flow rate from the microcomputer-generated curves was taken to assess the erythrocyte deformability index, as previously reported. Erythrocyte aggregation was measured using the Myrenne MA 1 aggregometer (Myrenne GmbH). The hematocrit was adjusted to 45% with autologous plasma using a microcentrifuge (15,000 g for 10 minutes). In the Myrenne aggregometer, the aggregation index was calculated from the surface area below the light intensity curve within a 5-second period at room temperature. The temperature was adjusted to 37°C. The PAI-1 antigen plasma levels were measured using an enzyme-linked immunosorbent assay test (Asserachrom PAI-1, Stago, Asnieres-sur-Seine, France). The vWF values were measured using a miniVIDAS analyzer (bioMérieux, Durham, North Carolina), as previously reported. The plasma norepinephrine and epinephrine levels were assayed using high-performance liquid chromatography. The blood count was determined using a Coulter counter (Coulter, Miami, Florida) and was assessed at basal conditions.
All participants provided informed consent, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Statistical analysis was performed using the Statistical Package for Social Sciences for Windows, version 19 (SPSS, Chicago, Illinois). Categorical variables are expressed as frequencies and percentages and continuous variables as the median and range or mean ± SD, as appropriate. The nonparametric Mann-Whitney U test for unpaired data was used to compare the variables between those with TC and the controls. To evaluate the differences in variables analyzed between baseline and after CPT in both the patients with TC and the controls, the nonparametric Wilcoxon rank sum test for paired data was used. Correlations among hemorheologic variables, catecholamines, and PAI-1 and vWF plasma levels were assessed using the Pearson correlation test. p Values <0.05 were considered statistically significant.
Results
No significant differences in the cardiovascular risk factors or baseline blood count parameters and fibrinogen values were found between the patients with TC and the controls. The hemorheologic and endothelial variables in the patients and controls before and after the CPT are listed in Table 1 and shown in Figures 1 to 3 . At baseline, a significantly lower erythrocyte deformability index (p <0.05) and greater PAI-1 levels (p <0.05) were found in patients with previous TC compared to the controls ( Table 1 and Figures 1 and 3 ). After the CPT, significant variations in all hemorheologic variables, endothelial markers, and catecholamines were observed in the patients with TC and the control group ( Table 1 and Figures 1 to 3 ), except for WBV at 0.512 s −1 , erythrocyte aggregation, and PAI-1 plasma in the controls. In the patients with TC, the CPT caused significantly greater values of WBV at 94.5 s −1 (p <0.05) and PAI-1 and vWF levels (p <0.01) and a lower erythrocyte deformability index (p <0.01) compared to those in the controls.
| Age (y) | WBV 0.512 s −1 (mPa·s) | WBV 94.5 s −1 (mPa·s) | PLV (mPa·s) | DI | EA | PAI-1 (ng/ml) | vWF (IU/dl) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | After CPT | Baseline | After CPT | Baseline | After CPT | Baseline | After CPT | Baseline | After CPT | Baseline | After CPT | Baseline | After CPT | ||
| Pt. No. | |||||||||||||||
| 1 | 31 | 14.0 | 18.2 | 3.39 | 3.68 | 1.24 | 1.38 | 7.9 | 5.3 | 3.1 | 3.2 | 15 | 17 | 127 | 134 |
| 2 | 65 | 19.5 | 22.7 | 3.64 | 3.91 | 1.23 | 1.28 | 10.1 | 1.8 | 2.9 | 3.2 | 11 | 13 | 221 | 225 |
| 3 | 65 | 17.2 | 22.8 | 4.14 | 4.43 | 1.28 | 1.38 | 10.6 | 6.2 | 4.3 | 4.7 | 13 | 21 | 91 | 162 |
| 4 | 65 | 15.5 | 24.4 | 3.46 | 4.34 | 1.44 | 1.80 | 7.2 | 1.8 | 2.0 | 2.2 | 19 | 37 | 166 | 218 |
| 5 | 66 | 15.2 | 17.6 | 4.61 | 4.69 | 1.38 | 1.38 | 11.5 | 9.5 | 2.3 | 2.7 | 6 | 31 | 245 | 251 |
| 6 | 67 | 16.9 | 17.6 | 4.00 | 4.31 | 1.27 | 1.34 | 12.7 | 1.8 | 1.5 | 2.7 | 10 | 30 | 81 | 220 |
| 7 | 71 | 20.2 | 21.0 | 4.15 | 4.36 | 1.38 | 1.40 | 9.6 | 1.6 | 3.6 | 3.8 | 16 | 26 | 163 | 208 |
| 8 | 71 | 18.2 | 22.2 | 4.53 | 4.73 | 1.35 | 1.36 | 13.6 | 3.8 | 3.3 | 3.8 | 23 | 45 | 253 | 317 |
| 9 | 71 | 16.5 | 19.4 | 3.74 | 3.88 | 1.36 | 1.44 | 11.2 | 3.1 | 2.3 | 2.5 | 19 | 23 | 203 | 233 |
| 10 | 74 | 18.0 | 25.6 | 3.58 | 4.38 | 1.05 | 1.32 | 10.3 | 5.0 | 2.2 | 2.7 | 18 | 38 | 179 | 270 |
| 11 | 78 | 16.7 | 21.5 | 4.59 | 4.79 | 1.53 | 1.65 | 8.6 | 2.8 | 3.8 | 4.9 | 20 | 71 | 222 | 236 |
| 12 | 79 | 18.2 | 25.8 | 3.86 | 3.99 | 1.28 | 1.33 | 11.0 | 7.6 | 2.1 | 2.4 | 11 | 25 | 143 | 187 |
| 13 | 80 | 19.4 | 21.7 | 3.85 | 4.35 | 1.22 | 1.33 | 5.2 | 3.1 | 2.2 | 2.9 | 15 | 18 | 159 | 203 |
| 14 | 80 | 17.1 | 23.4 | 3.65 | 4.23 | 1.22 | 1.28 | 12.3 | 3.8 | 2.2 | 2.7 | 23 | 46 | 182 | 245 |
| 15 | 82 | 16.3 | 24.3 | 3.73 | 3.99 | 1.36 | 1.50 | 6.5 | 2.2 | 3.2 | 3.5 | 11 | 35 | 295 | 310 |
| 16 | 83 | 16.7 | 18.3 | 4.20 | 4.33 | 1.41 | 1.50 | 6.1 | 2.8 | 3.5 | 3.9 | 14 | 29 | 150 | 203 |
| 17 | 84 | 16.3 | 20.5 | 3.62 | 4.19 | 1.32 | 1.38 | 12.7 | 5.9 | 4.5 | 4.8 | 22 | 27 | 86 | 263 |
| Control No. | |||||||||||||||
| 1 | 56 | 20.6 | 21.7 | 3.70 | 3.81 | 1.23 | 1.28 | 11.8 | 7.5 | 2.9 | 2.9 | 8 | 10 | 159 | 183 |
| 2 | 61 | 11.9 | 13.2 | 3.27 | 3.50 | 1.31 | 1.44 | 9.6 | 1.8 | 3.5 | 3.7 | 12 | 11 | 97 | 175 |
| 3 | 62 | 15.7 | 19.2 | 3.39 | 3.91 | 1.33 | 1.40 | 10.8 | 11.3 | 2.4 | 3.6 | 15 | 18 | 147 | 169 |
| 4 | 64 | 14.2 | 17.5 | 3.32 | 3.60 | 1.30 | 1.52 | 14.6 | 9.5 | 3.1 | 3.0 | 8 | 10 | 85 | 120 |
| 5 | 66 | 21.7 | 19.5 | 4.71 | 4.76 | 1.38 | 1.43 | 14.6 | 10.4 | 3.5 | 3.5 | 12 | 10 | 147 | 165 |
| 6 | 70 | 16.0 | 19.2 | 3.69 | 3.68 | 1.28 | 1.40 | 16.0 | 10.4 | 3.0 | 3.2 | 6 | 22 | 101 | 109 |
| 7 | 76 | 21.9 | 23.0 | 3.99 | 4.05 | 1.35 | 1.45 | 13.8 | 4.0 | 1.9 | 2.8 | 6 | 8 | 149 | 244 |
| 8 | 79 | 20.7 | 21.5 | 3.73 | 3.83 | 1.36 | 1.40 | 11.8 | 6.5 | 3.0 | 3.1 | 13 | 20 | 230 | 263 |
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