Incidence and clinical/laboratory correlates of early hypotension in takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is a form of acute myocardial inflammation, often triggered by catecholamine release surges, which accounts for approximately 10% of 'myocardial infarctions' in female patients above the age of 50. Its associated substantial risk of in-hospital mortality is mainly driven by the development of hypotension and shock. While hypotension is induced largely by factors other than low cardiac output, its precise cause is unknown, and clinical parameters associated with hypotension have not been identified previously. We therefore sought to identify the incidence and clinical/laboratory correlates of early hypotension in TTS. METHODS AND RESULTS: We analysed the in-hospital data of patients recruited to the South Australian TTS Registry. Associations between the development of hypotension, patient demographics, severity of the acute TTS attack, and key biochemical markers were sought. One hundred thirteen out of 319 patients (35%) were hypotensive (median systolic blood pressure 80 mmHg) during their index hospitalization. Development of hypotension preceded all in-hospital deaths (n = 8). On univariate analyses, patients who developed hypotension had lower left ventricular ejection fraction (P = 0.009), and higher plasma N-terminal pro brain natriuretic peptide and troponin-T concentrations (P = 0.046 and 0.008, respectively), all markers of severity of the TTS attack; hypotension also occurred less commonly in male than in female patients (P = 0.014). On multivariate linear regression analysis, female sex and lower left ventricular ejection fraction were independent correlates of the development of hypotension (P = 0.009 and 0.010, respectively). CONCLUSIONS: Early development of hypotension is very common in TTS, and its presence is associated with a substantial risk of in-hospital mortality. Hypotension is a marker of severe TTS attacks and occurs more commonly in female TTS patients.

Prolonged suppression of the anti-oxidant/anti-inflammatory effects of BNP post-Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) episodes are primarily initiated by 'pulse' release of catecholamines inducing neutrophil infiltration and myocardial inflammation in susceptible individuals (largely ageing women). Evidence of myocardial inflammation and associated energetic impairment persists for ≥ 3 months post-acute TTS episodes, suggesting the existence of additional 'perpetuating' mechanisms. The effects of B-type natriuretic peptide (BNP) in suppressing superoxide (O2- ) release from neutrophils are transiently impaired in acute heart failure. We also evaluated the extent and duration of BNP-induced suppression of O2- release post-TTS. METHODS AND RESULTS: TTS patients were studied acutely (n = 34) and 3 months thereafter (n = 13) and compared with control subjects (n = 25). O2- generation from neutrophils, triggered by N-formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate, and its suppression by BNP, were measured in vitro. Determinants of variability in BNP effect were sought via univariate and multivariate analyses. Relative to control subjects, in TTS patients, BNP suppression of both phorbol myristate acetate and N-formyl-methionyl-leucyl-phenylalanine-induced O2- release was impaired acutely (P < 0.05 for both); this did not improve over the 3-month recovery period, despite treatment with conventional anti-failure medication in 85% of patients. No significant correlates of BNP effect (other than TTS) were identified. CONCLUSIONS: (1) While TTS is associated with marked and prolonged release of BNP, there is virtually total loss of the ability of BNP to suppress neutrophil O2- release and its impact on tissue inflammation. (2) BNP responses do not recover for at least 3 months post-attacks, suggesting that this might contribute to perpetuation of myocardial inflammation in TTS patients.

Incremental "Therapeutic" Myocardial Exposure to Catecholamines: Incidence and Impact in Takotsubo Syndrome.

BACKGROUND: Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial ß2-adrenoceptor level. Cases of TS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this "iatrogenic" form of TS. METHODS/RESULTS: Patients' data from a regional registry of 301 consecutive cases of TS were evaluated after exclusion of patients (n = 20) in whom TS had occurred in association with life threatening extracardiac disease states. A total of 55 (18%) of patients were identified as having antecedent exposure to potentially "iatrogenic" agents (tricyclic antidepressants in 24 cases, ß2-adrenoceptor agonists in 15). Demographics, including proportion of male patients, did not differ significantly between patients with and without "iatrogenic" TS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1149 pmol/L vs 938 pmol/L; p = 0.03). Long-term survival (median follow-up 3 years) was marginally (p = 0.13) worse for patients with "iatrogenic" TS. CONCLUSION: Potentially iatrogenic precipitation of TS attacks (via iatrogenic elevation of catecholamine levels and ß2-adrenoceptor stimulation) is common, associated with greater elevation of plasma normetanephrine concentrations, and also with a trend towards increased long-term mortality when compared to the remainder of TS patients.

The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome.

BACKGROUND: Takotsubo Syndrome(TTS), contrary to historical reports, is now increasingly recognised to be associated with substantial mortality and morbidity, both in the short- and long-term. Although TTS is often precipitated by a catecholamine "pulse", in-hospital hypotension is a common occurrence, increasing the risk of mortality. Furthermore, despite the transient catecholamine stimulus, there is increasing evidence that there are significant long term sequelae, including persistently impaired left ventricular(LV) systolic dysfunction, myocardial oedema with fibrosis, as well as persistent impairment of quality of life. A definitive therapeutic option to limit the extent of initial myocardial injury, and to accelerate recovery in TTS is therefore justified. However to date, there has been a lack of prospective studies in this area. DESIGN AND RATIONALE: NACRAM is a multi-centre, randomised, placebo-controlled trial, sequentially testing early use of intravenous N-acetylcysteine(NAC), followed by/or oral ramipril for 12 weeks. The rationale for utilising these agents is related to their effects on limiting nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein(TXNIP); both processes fundamental to the pathogenesis of TTS. END POINTS: NACRAM is assessing resolution of myocardial oedema on cardiac magnetic resonance imaging(CMR), improvements in LV systolic function as measured by global longitudinal strain(GLS) on echocardiography, quality of life, and inflammatory markers. DISCUSSION: To the best of our knowledge, NACRAM will be the first prospective study to help definitively evaluate a therapeutic option in acute attacks of TTS.

Antecedent cancer in Takotsubo syndrome predicts both cardiovascular and long-term mortality.

BACKGROUND: Takotsubo syndrome (TTS), primarily an acute myocardial inflammatory condition engendered by catecholamine exposure, is associated with similar long-term mortality rates to those of patients with acute myocardial infarction. However, there is increasing evidence of a nexus between TTS and underlying malignancies:- many patients have antecedent cancer (A/Ca), while incremental risk of late cancer-related death has also been reported. PURPOSE: To evaluate potential interactions between A/Ca among TTS patients and both early and late clinical course. METHODS: Three hundred forty-six consecutive TTS patients [aged 69 ± 13 (SD) years, males: 8.2%] were prospectively followed up for a median duration of 4.1 (IQR 2.2-6.4) years. Associations between A/Ca and severity of acute attacks, in-hospital complications and long-term death rates were sought utilising univariate analyses followed by multiple logistic regression analysis. RESULTS: A/Ca (present in 16.8% of patients) was associated with (i) greater elevation of hs-CRP and NT-proBNP concentrations (p = 0.01 and 0.04, respectively), (ii) more complicated in-hospital clinical course, with major adverse cardiac events (MACE) in 30.9% of patients, compared to 18.2% in non-A/Ca patients (p = 0.04). Long-term all-cause mortality rate was also greater [hazard ratio (HR) = 2.4, p = 0.0001] in A/Ca patients, with an excess cardiovascular (CVS) fatality rate (HR = 3.1, p = 0.001). On multivariate analysis, male gender, peak plasma concentrations of normetanephrine and hs-CRP, early arrhythmias and development of shock, but not A/Ca per se, were all independently associated with increased long-term mortality rate. Furthermore, patients discharged on ß-adrenoceptor antagonists (ßBl) or angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARB) had lower long-term mortality rates (ß = - 0.2, p = 0.01; ß = - 0.14, p = 0.05, respectively). CONCLUSIONS: (1) A/Ca is associated with greater clinical severity of initial TTS attacks and substantially greater long-term CVS-related as well as all-cause mortality.(2) Post-discharge therapy with either ßBl or ACEi/ARB is associated with reductions in long-term mortality rates.Overall, the current data suggest operation of substantial interactions between neoplasia and TTS, both at the level of pathogenesis and of outcomes.

Relation of delayed recovery of myocardial function after takotsubo cardiomyopathy to subsequent quality of life.

Takotsubo cardiomyopathy (TTC) has generally been regarded as a relatively transient disorder, characterized by reversible regional left ventricular systolic dysfunction. However, most patients with TTC experience prolonged lassitude or dyspnea after acute attacks. Although this might reflect continued emotional stress, myocardial inflammation and accentuated brain-type natriuretic peptide (BNP) release persist for at least 3 months. We therefore tested the hypotheses that this continued inflammation is associated with (1) persistent contractile dysfunction and (2) consequent impairment of quality of life. Echocardiographic parameters (global longitudinal strain [GLS], longitudinal strain rate [LSR], and peak apical twist [AT]) were compared acutely and after 3 months in 36 female patients with TTC and 19 age-matched female controls. Furthermore, correlations were sought between putative functional anomalies, inflammatory markers (T2 score on cardiovascular magnetic resonance, plasma NT-proBNP, and high-sensitivity C-reactive protein levels), and the physical composite component of SF36 score (SF36-PCS). In TTC cases, left ventricular ejection fraction returned to normal within 3 months. GLS, LSR, and AT improved significantly over 3-month recovery, but GLS remained reduced compared to controls even at follow-up (-17.9 ± 3.1% vs -20.0 ± 1.8%, p = 0.003). Impaired GLS at 3 months was associated with both persistent NT-proBNP elevation (p = 0.03) and reduced SF36-PCS at ≥3 months (p = 0.04). In conclusion, despite normalization of left ventricular ejection fraction, GLS remains impaired for at least 3 months, possibly as a result of residual myocardial inflammation. Furthermore, perception of impaired physical exercise capacity ≥3 months after TTC may be explained by persistent myocardial dysfunction.

Dissociation of early shock in takotsubo cardiomyopathy from either right or left ventricular systolic dysfunction.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS). METHODS: We evaluated 102 consecutive TTC patients with acute transthoracic echocardiography (TTE) to detect RV hypokinesis. Correlates of hypotension, shock and PHS were identified by univariate and multivariate analyses. RESULTS: Of the 102 patients evaluated, 33% had RV hypokinesis but only 9% had extensive RV involvement. Within the first 24 hours of admission, severe hypotension (systolic blood pressure (SBP) ≤ 90 mmHg) occurred in 21% of the patients and shock (hypotension + peripheral organ hypo-perfusion) in 16.6% of cases. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in PHS. On the other hand, RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction. CONCLUSIONS: In TTC, RV hypokinesis occurs in approximately 33% of cases and correlates with more severe LV wall motion abnormality but not with development of hypotension or shock. These data therefore reinforce previous findings that hypotension/shock in TTC are not purely by impaired cardiac output.

Dissociation between severity of takotsubo cardiomyopathy and presentation with shock or hypotension.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is increasingly well-recognized as a cause of chest-pain syndromes, especially in aging females. The most common complications of TTC occur in the first 24 hours post onset of symptoms and include shock and/or arrhythmias. HYPOTHESIS: We tested the hypothesis that the severity of early hypotension in TTC reflects the extent of myocardial involvement and dysfunction. METHODS: In 80 consecutive TTC patients, correlates of blood pressure on the day of admission were sought via univariate followed by multivariate analysis. RESULTS: Mean systolic blood pressure (SBP) on day 1 was 120 ± 24 (SD) mm Hg. During the first 3 days of admission, 39% of patients had SBP <90 mm Hg, and 9% died and/or required intra-aortic balloon pump insertion. The extent of release of N-terminal pro-brain natriuretic peptide, with its potential correlate of associated vasodilator activity, varied inversely with pulmonary-artery saturation, a measure of cardiac output. However, there was no significant relationship between normetanephrine release and SBP. On multivariate analyses there was no significant relationship between SBP and (1) wall-motion score index (as an index of left-ventricular systolic dysfunction) or (2) T2 enhancement on cardiac magnetic resonance imaging and peak N-terminal pro-brain natriuretic peptide (as indices of myocardial inflammation). CONCLUSIONS: Although severe hypotension and shock occur commonly during acute stages of TTC, these complications are multifactorial in origin, probably representing a combination of impaired inotropic state and vasodilatation. Importantly, initial hypotension does not imply severe left ventricular inflammation or systolic dysfunction.

Can we make sense of takotsubo cardiomyopathy? An update on pathogenesis, diagnosis and natural history.

Takotsubo cardiomyopathy (TTC) is a form of reversible acute cardiac dysfunction of uncertain pathogenesis, which occurs predominantly in postmenopausal women, often with antecedent severe stress. Systolic dysfunction most commonly affects the apex of the left ventricle. There is considerable uncertainty regarding the pathogenesis of TTC and the optimal diagnostic methodology. Acute catecholamine release may play a component role, but the regional hypokinesis is associated with an acute inflammatory process, with resultant early release of brain natriuretic peptide (BNP) and N-terminal pro-BNP. As the diagnosis of TTC has largely been a process of exclusion, there has been considerable underdiagnosis. The combination of demographics, preceding history, ECG appearances and N-terminal pro-BNP elevation may provide the basis for improved early diagnosis. Complete recovery takes at least several months, with a risk of recurrent episodes. Efforts to delineate pathogenesis, expedite diagnosis and evaluate residual disability may assist in the development of appropriate treatment regimens.

N-terminal pro-brain natriuretic protein levels in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular (LV) systolic dysfunction independent of fixed coronary disease or coronary spastic pathogenesis. A number of investigators have documented marked elevation of natriuretic peptide levels at presentation in such patients. We sought to determine the pattern, extent, and determinants of the release of N-terminal pro-B type natriuretic peptide/B type natriuretic peptide (NT-proBNP/BNP) in patients with TTC. We evaluated NT-proBNP/BNP release acutely and during the first 3 months in 56 patients with TTC (96% women, mean age 69 ± 11 years). The peak plasma NT-proBNP levels were compared to the pulmonary capillary wedge pressure and measures of regional and global LV systolic dysfunction (systolic wall stress, wall motion score index, and LV ejection fraction) as potential determinants of NT-proBNP/BNP release. In patients with TTC, the plasma concentrations of NT-proBNP (median 4,382 pg/ml, interquartile range 2,440 to 9,019) and BNP (median 617 pg/ml, interquartile range 426 to 1,026) were substantially elevated and increased significantly during the first 24 hours after the onset of symptoms (p = 0.001), with slow and incomplete resolution during the 3 months thereafter. The peak NT-proBNP levels exhibited no significant correlation with either pulmonary capillary wedge pressure or systolic wall stress. However, the peak NT-proBNP level correlated significantly with the simultaneous plasma normetanephrine concentrations (r = 0.53, p = 0.001) and the extent of impairment of LV systolic function, as measured by the wall motion score index (r = 0.37, p = 0.008) and LV ejection fraction (r = -0.39, p = 0.008). In conclusion, TTC is associated with marked and persistent elevation of NT-proBNP/BNP levels, which correlated with both the extent of catecholamine increase and the severity of LV systolic dysfunction.