Takotsubo Syndrome: Finally Emerging From the Shadows?

It is now 30 years since Japanese investigators first described Takotsubo Syndrome (TTS) as a disorder occurring mainly in ageing women, ascribing it to the impact of multivessel coronary artery spasm. During the intervening period, it has become clear that TTS involves relatively transient vascular injury, followed by prolonged myocardial inflammatory and eventually fibrotic changes. Hence symptomatic recovery is generally slow, currently an under-recognised issue. It appears that TTS is induced by aberrant post-ß2-adrenoceptor signalling in the setting of "surge" release of catecholamines. Resultant activation of nitric oxide synthases and increased inflammatory vascular permeation lead to prolonged myocardial infiltration with macrophages and associated oedema formation. Initially, the diagnosis of TTS was made via exclusion of relevant coronary artery stenoses, plus the presence of regional left ventricular hypokinesis. However, detection of extensive myocardial oedema on cardiac MRI imaging offers a specific basis for diagnosis. No adequate methods are yet available for definitive diagnosis of TTS at hospital presentation. Other major challenges remaining in this area include understanding of the recently demonstrated association between TTS and antecedent cancer, the development of effective treatments to reduce risk of short-term (generally due to shock) and long-term mortality, and also to accelerate symptomatic recovery.

Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI.

OBJECTIVE: Tako-Tsubo cardiomyopathy (TTC) is associated with regional left ventricular dysfunction, independent of the presence of fixed coronary artery disease. Previous studies have used T2-weighted cardiac MRI to demonstrate the presence of periapical oedema. The authors sought to determine the distribution, resolution and correlates of oedema in TTC. PATIENTS: 32 patients with TTC were evaluated at a median of 2 days after presentation, along with 10 age-matched female controls. Extent of oedema was quantified both regionally and globally; scanning was repeated in patients with TTC after 3 months. Correlations were sought between oedema and the extent of hypokinesis, catecholamine release, release of N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and markers of systemic inflammatory activation (high-sensitivity C-reactive protein and platelet response to nitric oxide). RESULTS: In the acute phase of TTC, T2-weighted signal intensity was greater at the apex than at the base (p<0.0001) but was nevertheless significantly elevated at the base (p<0.0001), relative to control values. Over 3 months, T2-weighted signal decreased substantially, but remained abnormally elevated (p<0.02). The regional extent of oedema correlated inversely with radial myocardial strain (except at the apex). There were also direct correlations between global T2-weighted signal and (1) plasma normetanephrine (r=0.39, p=0.04) and (2) peak NT-proBNP (r=0.39, p=0.03), but not with systemic inflammatory markers. CONCLUSIONS: TTC is associated with slowly resolving global myocardial oedema, the acute extent of which correlates with regional contractile disturbance and acute release of both catecholamines and NT-proBNP.

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.

Secondary prevention for acute coronary syndrome in rural South Australia: are drugs best? What about the rest?

INTRODUCTION: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality worldwide. Current Australian clinical guidelines recommend all patients with ACS receive comprehensive secondary prevention services to address this burden. Optimal patient outcomes rely on the timely and effective implementation of proven therapies and for secondary prevention to be successful, pharmacological interventions must be combined with cardiovascular disease (CVD) risk factor identification and management. The ability to implement clinical guidelines is also reliant on available resources, yet many rural populations in Australia do not have access to structured secondary prevention services, and the level of support available to them in the form of unstructured services is unclear. Our aim was to examine the scope of secondary prevention in a 'significantly restricted' rural region of South Australia that does not have access to structured secondary prevention services. METHODS: A retrospective analysis of medical records was undertaken to identify documented evidence of assessment and intervention for medical, lifestyle and behavioural CVD risk factors in hospital and at follow up in general practice (GP) clinics. Eligible participants were patients admitted to hospital in the Riverland Region of South Australia with myocardial infarction over a 12 month period. Of 77 eligible participants, permission was received to access the medical records of 55 patients in the hospital setting, and 34 of these 55 patients in GP clinic follow up. RESULTS: Most patients received baseline assessment for previous AMI (98%), history of hypertension (82%), history of diabetes (78%), and smoking status (76%). Most poorly documented was history of dyslipidaemia (53%) and obesity/ overweight (2%). Prescribing rates for recommended ACS medications at the time of hospital discharge were aspirin (90%), beta blockers (55%), ACE inhibitors (42%), lipid lowering medication (66%) and clopidogrel (64%). Overall prescribing rates in the 12 month study period rose to 80% or higher for all recommended medications. There was no evidence of interventions for smoking and obesity/ overweight in the hospital setting and 45% of smokers in the GP clinic setting received quit advice. Measurement of biomedical risk factors (blood lipid analysis and blood glucose levels) was suboptimal, and there was no evidence of a written action plan for chest pain for any participants. CONCLUSIONS: Unstructured services provided some of the recommended elements of secondary prevention. However, deficits in care exist that have the potential to negatively impact patient outcomes in this already disadvantaged population. Future research needs to focus on the extent to which this and other rural and remote health care services are working within current clinical guidelines for the management of ACS, and subsequent patient outcomes. Urgent consideration must also be given to the introduction and evaluation of a more structured and consistent approach in this and other rural and remote regions of Australia. The development of rehabilitation and prevention services that build on existing strengths and resources have the potential to widen access, enhance current services and ensure care is based on best practice guidelines. This in turn may reduce the burden of CVD and improve the overall health and quality of life for patients in rural and remote Australia.

Unstructured cardiac rehabilitation and secondary prevention in rural South Australia: does it meet best practice guidelines?

Comprehensive cardiac rehabilitation programs that address risk factors, psychological problems, and physical activity are essential in optimizing health and reducing the risk of further cardiac events. Behavioural and lifestyle modification support offered through these programs is predicated on initial identification of risk. Many rural populations in Australia do not have access to structured cardiac rehabilitation (CR) programs, and the level of support available to them in the form of unstructured CR is unclear. A retrospective analysis of medical records of patients presenting to hospital with myocardial infarction in rural South Australia over a 12 month period was undertaken to identify documented evidence of assessment of and intervention for lifestyle and behavioural risk factors in-hospital and at follow up in general practice (GP) clinics. Of 77 eligible participants, permission was received to access the medical records of 55 patients in the hospital setting, and 34 of these 55 patients in GP clinic follow up. Documented evidence of assessment of modifiable risk factors was inadequate for the majority of participants, with the exception of smoking status, hypertension and diabetes. This suggests that the majority of these participants did not receive lifestyle and behavioural interventions in line with current National Heart Foundation Recommendations for Cardiac Rehabilitation. Barriers to comprehensive CR and secondary prevention services in Australia must be addressed, particularly in high risk rural and remote populations. Future research must focus on the ongoing monitoring and evaluation of rural health care services to analyse existing levels of CR and secondary prevention to ensure current guidelines are being implemented, to support the further development and resourcing of CR services and to evaluate the subsequent impact on patient outcomes.

The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes mediation by superoxide production, resolution with intensive insulin administration.

OBJECTIVES: This study sought to assess the determinants of platelet nitric oxide (NO) responsiveness in diabetic patients admitted with acute coronary syndromes (ACS) and the short-term effects of aggressive glycemic control on these factors. BACKGROUND: Hyperglycemia is an independent risk factor for mortality in both diabetic patients and nondiabetic patients with ACS. The mechanism(s) underlying this observation and potential benefit from its correction remain uncertain. Although a reduction in NO bioavailability has been proposed, this remains untested in the ACS setting. METHODS: A total of 76 diabetic patients with ACS were studied. Putative correlations between admission blood sugar level (BSL), inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP), and superoxide (O2-) were assessed. Hyperglycemic patients (n = 60) were randomized to acute glycemic control with intravenous versus subcutaneous insulin, and changes in the aforementioned parameters were compared. Plasma levels of the endogenous inhibitor of NO synthase asymmetric dimethylarginine (ADMA) were also monitored. RESULTS: There was an inverse correlation between admission BSL and both platelet SNP response (p = 0.007) and ADMA levels (p = 0.045), and a positive correlation with O2- generation (p < 0.001). Intravenous insulin infusion resulted in a greater reduction (p < 0.001) in BSL, differentially improved platelet responsiveness to SNP (p = 0.049), and decreased O2- (p < 0.001) and ADMA levels (p = 0.049). CONCLUSIONS: A component of platelet dysfunction in diabetic patients with ACS is impaired responsiveness to the anti-aggregatory effects of NO, probably reflecting increased NO clearance by O2-. This phenomenon is reversed by acute aggressive glycemic control. These findings provide a further rationale for use of insulin therapy in acute myocardial infarction and suggest its extension to ACS patients.

Failed reperfusion after thrombolytic therapy: recognition and management.

BACKGROUND: Failed reperfusion after thrombolysis occurs in as many as 30% of patients with acute myocardial infarction (MI). Furthermore, some patients have incomplete tissue perfusion despite reperfusion of the infarct-related artery. Close assessment of the efficacy of thrombolytic administration in people with evolving acute MI is necessary, particularly with regard to myocardial perfusion status, because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies. PURPOSE AND METHOD: This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity. CONCLUSION: The early detection of failed reperfusion is critical if incremental strategies to enhance myocardial salvage are to be considered. Continuous ST-segment monitoring is a relatively inexpensive, reliable, and accurate tool for assessing real-time myocardial perfusion.