C. Zeitz

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.

Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema

BACKGROUND Nitrates are superior to furosemide in the management of acute pulmonary edema associated with myocardial infarction; however, their role in the absence of infarction is unclear. METHODS AND RESULTS A randomized comparison was undertaken of the relative effectiveness of primary therapy with either intravenous morphine/furosemide (men/women; n = 32) or nitroglycerin/N-acetylcysteine (NTG/NAC; n = 37) in consecutive patients with acute pulmonary edema. The primary end point was change in PaO2/FIO2 over the first 60 minutes of therapy. Secondary end points were needed for mechanical respiratory assistance (ie, continuous positive airway pressure via mask or intubation and ventilation) and changes in other gas exchange parameters. Both treatment groups showed improvement in oxygenation after 60 minutes of therapy; however, this reached statistical significance only with NTG/NAC therapy. There was no significant difference between groups in the assessed parameters (95% CI for differences in Pao2/FIO2: furosemide/morphine -12 to 23 and NTG/NAC 4 to 44), a finding also confirmed in 32 patients presenting with respiratory failure. Only 11% of the study group required mechanical ventilatory assistance (continuous positive airway pressure in 4 patients and intubation and ventilation in 3 patients). CONCLUSIONS NTG/NAC therapy is as effective as furosemide/morphine in the initial management of acute pulmonary edema, regardless of the presence or absence of respiratory failure. The necessity for mechanical ventilatory assistance is infrequent in these patients, regardless of the initial medical treatment regimen.

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.

Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ace2) in angiotensin peptide metabolism in the human coronary circulation

Objective To investigate the role of angiotensin-converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. Methods Angiotensin I and angiotensin II, and their respective carboxypeptidase metabolites, angiotensin-(1–9) and angiotensin-(1–7), were measured in arterial and coronary sinus blood of heart failure subjects receiving angiotensin-converting enzyme (ACE) inhibitor therapy and in normal subjects not receiving ACE inhibitor therapy. In addition, angiotensin I, angiotensin II and angiotensin-(1–7) were measured in arterial and coronary sinus blood of subjects with coronary artery disease before, and at 2, 5 and 10 min after, intravenous administration of ACE inhibitor. Results In comparison with normal subjects, heart failure subjects receiving ACE inhibitor therapy had a greater than 40-fold increase in angiotensin I levels, but angiotensin-(1–9) levels were low (1–2 fmol/ml), and similar to those of normal subjects. Moreover, angiotensin-(1–7) levels increased in parallel with angiotensin I levels and the angiotensin-(1–7)/angiotensin II ratio increased by 7.5-fold in coronary sinus blood. Intravenous administration of ACE inhibitor to subjects with coronary artery disease rapidly decreased angiotensin II levels by 54–58% and increased angiotensin I levels by 2.4- to 2.8-fold, but did not alter angiotensin-(1–7) levels or net angiotensin-(1–7) production across the myocardial vascular bed. Conclusions The failure of angiotensin-(1–9) levels to increase in response to increased angiotensin I levels indicated little role for ACE2 in angiotensin I metabolism. Additionally, the levels of angiotensin-(1–7) were more linked to those of angiotensin I than angiotensin II, consistent with its formation by endopeptidase-mediated metabolism of angiotensin I, rather than by ACE2-mediated metabolism of angiotensin II.

Heart failure, ventricular dysfunction and risk factor prevalence in Australian Aboriginal peoples: the Heart of the Heart Study

Background Limited strategies have been developed to evaluate and address the alarming discrepancy in early mortality between Indigenous and non-Indigenous populations. Objective To assess heart failure (HF), HF risk factors and document cardiac characteristics in an Australian Aboriginal population. Design, setting, participants Adults were enrolled across six Aboriginal communities in Central Australia. They undertook comprehensive cardiovascular assessments, including echocardiography, to determine HF status, asymptomatic ventricular dysfunction and underlying risk factor profile. Results Of 436 participants (mean age 44±14 years; 64% women) enrolled, 5.3% (95% CI 3.2% to 7.5%) were diagnosed with HF, only 35% of whom had a pre-existing HF diagnosis. Asymptomatic left ventricular dysfunction (ALVD) was seen in 13% (95% CI 9.4% to 15.7%) of the population. Estimates of HF risk factor prevalence were as follows: body mass index (BMI) ≥30 kg/m2 42%, hypertension 41%, diabetes mellitus 40%, coronary artery disease (CAD) 7% and history of acute rheumatic fever or rheumatic heart disease 7%. In logistic regression analysis (after adjustment for age and gender), HF was associated with CAD (OR=9.6, p<0.001), diabetes (OR=5.4, p=0.002), hypertension (OR=4.8, p=0.006), BMI ≥30 kg/m2 (OR=2.9, p=0.02), acute rheumatic fever or rheumatic heart disease (OR=5.6, p=0.001) and B-type natriuretic peptide (OR=1.02, p<0.001). Conclusion The burden of HF, ALVD and risk factors in this population was extremely high. This study highlights potentially modifiable targets on which to focus resources and screening strategies to prevent HF in this high-risk Indigenous population.

Using the ability to perform CPR as a standard of fitness: a consideration of the influence of aging on the physiological responses of a select group of first aiders performing cardiopulmonary resuscitation.

OBJECTIVE Previous research has suggested that the physical demands of performing cardiopulmonary resuscitation (CPR) are relatively low. However, the subjects studied have generally been of a young age. The aim of this study was to test the hypothesis, in null form, that the physiological responses to the performance of single operator CPR for 10 min are independent of age. Confirmation of the hypothesis would allow the use of a period of time performing CPR as a socially non-discriminatory means of testing ability across a wide spectrum of age. DESIGN 33 St. John Operations Branch members (a sample of convenience), aged between 18 and 65 years, were examined whilst performing 10 min of single operator CPR on a manikin at St. John Ambulance Headquarters, Adelaide, South Australia. Heart rate and cardiac rhythm were monitored continuously. Blood pressure was recorded at baseline and the end of the 3rd, 6th and 9th min of CPR. Subjects also rated their perceived level of activity using the 15-point Borg rating scale every 3 min and at the end of the test. RESULTS The calculated rate-pressure product did not vary significantly with age, either at rest or in response to performing CPR. The rate-pressure product increased significantly (P < 0.05) whilst performing CPR. There was no effect of age on the perceived level of exertion, which also increased significantly during CPR as compared with rest. CONCLUSION There was no significant effect of age on the physiological responses to the performance of 10 min of single operator CPR in this select group.

Cardiometabolic risk and disease in Indigenous Australians: The heart of the heart study

OBJECTIVES This study assessed the burden and determinants of cardiovascular and metabolic risk in a community sample of high risk Indigenous Australians. BACKGROUND Indigenous Australians are over-represented in the most disadvantaged strata of Australian society. The role of psychosocial and socioeconomic factors in patterning cardiometabolic disease in this population is unclear. METHODS The Heart of the Heart Study was a cross sectional study of 436 Aboriginal adults from remote, urban and peri-urban communities around Alice Springs (Northern Territory, Australia). Participants underwent detailed assessments of socio-demographic, psychosocial, cardiovascular and metabolic status. RESULTS Individuals with depression were twice as likely to have cardiovascular disease (OR 2.03; 1.07-3.88; p<0.05). Chronic kidney disease (39.7%, 37.2% and 18.2%) and diabetes (28.4%, 34.0% and 19.2%) were more common in peri-urban and remote compared to urban communities. Cardiovascular disease did not vary across locations (p=0.069), but coronary artery disease did (p=0.035 for trend). Unemployed individuals were more likely to have cardiovascular disease (OR 2.32; 1.33-4.06; p<0.001). Socioeconomic gradients in coronary artery disease, all cardiovascular disease and diabetes, as measured by income, operated differentially across locations (p for location/socioeconomic status interactions 0.002; 0.01 and 0.04 respectively). CONCLUSION Participants had high rates of pre-existing cardiovascular disease, diabetes and chronic kidney disease. Cardiovascular risk in these communities was associated with psychosocial factors and socioeconomic indicators. However, gradients operated differentially across location. These data provide a strong foundation for better understanding key drivers of increased levels of cardiovascular and other common forms of non-communicable disease in Indigenous people.

Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM trial [N-acetylcysteine in acute myocardial infarction])

Background: Contemporary ST-segment–elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging–assessed infarct size. Secondary end points included cardiac magnetic resonance–determined myocardial salvage and creatine kinase kinetics. Results: Of 112 randomized patients with ST-segment–elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance–assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37–79) compared with placebo (27%; interquartile range, 14–42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). Conclusions: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.

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.

ST/T wave changes during acute coronary syndrome presentation in patients with the coronary slow flow phenomenon

Article history:Received 20 October 2010Accepted 23 October 2010Available online 3 December 2010Keywords:Coronary slow flow phenomenonECG abnormalitiesAcute coronary syndromeMyocardial ischaemia⁎ Corresponding author. Cardiology Unit, The Queen Elizabeth Hospital, 28 Wood-ville Road, Woodville, SA 5011, Australia. Tel.: +61 8222 6740; fax: +61 8222 6042.E-mail address: john.beltrame@adelaide.edu.au (J.F. Beltrame).Table 1Baseline characteristics.CSFP ControlsNumber 37 20Age (Mean±SD) 49±14.6*years 54.8±13.5 yearsCV risk factorsMales 27 (73%)* 9 (45%)Smoking History 19 (51%) 5 (25%)Hypertension 19 (51%)** 0 (0%)Cholesterol 20 (54%)* 6 (30%)Diabetes 9 (24%) 1 (5%)Pain-free Resting ECGSinus Rhythm 33 (100%) 20 (100%)Heart Rate 65±10 bpm 60±7 bpmResting ST changes 13 (39%)** 0 (0%)Inferior ST Elevation 9 (27%)* 0 (0%)Anterior ST Elevation 1 (3%) 0 (0%)Resting T wave changes 5 (15%) 1 (5%)Inferior T wave change 2 (6%) 1 (3%)Anterior T wave change 2 (6%) 0 (0%)QTc Interval 426±33 msec 410±10 msec*pb0.05 or **pb0.01; significant difference between CSFPs and healthy controls.