C. Neil

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI)

Aim Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this doubleblind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). Methods and results A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6–8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6–8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size −0.7% 95% CI: −2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6–8 days and at 6 months and final infarct size (FIS) measured at 6 months. Conclusions Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.

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.

The breathing heart — Mitochondrial respiratory chain dysfunction in cardiac disease

The relentlessly beating heart has the greatest oxygen consumption of any organ in the body at rest reflecting its huge metabolic turnover and energetic demands. The vast majority of its energy is produced and cycled in form of ATP which stems mainly from oxidative phosphorylation occurring at the respiratory chain in the mitochondria. Apart from energy production, the respiratory chain is also the main source of reactive oxygen species and plays a pivotal role in the regulation of oxidative stress. Dysfunction of the respiratory chain is therefore found in most common heart conditions. The pathophysiology of mitochondrial respiratory chain dysfunction in hereditary cardiac mitochondrial disease, the ageing heart, in LV hypertrophy and heart failure, and in ischaemia-reperfusion injury is reviewed. We introduce the practising clinician to the complex physiology of the respiratory chain, highlight its impact on common cardiac disorders and review translational pharmacological and non-pharmacological treatment strategies.

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.

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

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.

No association of G‐protein‐coupled receptor kinase 5 or β‐adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort

Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G‐protein‐coupled receptor kinase 5 (GRK5) gene, as well as in the β1‐adrenergic receptor (β1AR) and β2AR.

Occurrence of Tako-Tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors

Tako-Tsubo cardiomyopathy (TTC) occurs particularly in post-menopausal women, being precipitated in many cases by severe emotional stress. We describe six patients in whom TTC occurred in association with therapeutic ingestion or overdose of the serotonin/noradrenaline reuptake inhibitor venlafaxine, or its metabolite desvenlafaxine. Importantly, two of the six cases were not post-menopausal women. An increased risk of TTC may account for some of the reported cardiovascular adverse effects of venlafaxine and similar agents.

The effects of resistance training on muscle strength, quality of life and aerobic capacity in patients with chronic heart failure — A meta-analysis

BACKGROUND Resistance training (RT) has been utilised to target muscle dysfunction associated with Chronic Heart Failure (CHF). However, there is limited meta-analysis evidence to support its use as a standalone therapy. This meta-analysis examined the effects of RT on muscle strength (one repetition maximum, 1RM and Peak Torque), aerobic capacity (VO2peak and 6min walk distance) and quality of life (QoL) in patients with CHF. METHODS We searched Medline, EMBASE, Cochrane and CINAHL for studies published up to July 2016, combining terms related to the population (eg, heart failure, CHF) with terms for the intervention (eg, resistance, strength training) and the outcomes (eg, QoL, VO2peak,strength, aerobic capacity). RESULTS Ten studies including 240 participants were included in our meta-analysis (aged 48-76years, Ejection Fraction 18-37%). Training duration ranged from 8 to 24weeks and intensity up to 80% of 1RM. RT increased 1RM (standardised change score=0.60; 95% Confidence Interval: 0.43, 0.77) but not strength measured via peak torque at 60°/s-1 and 180°/s-1. RT increased VO2peak (CSMD: 2.71ml/kg/min; 1.96, 3.45) and QoL (CSMD: -5.71; -9.85, -1.56). CONCLUSION RT as a single intervention can increase muscle strength, aerobic capacity and QoL in patients with CHF and may offer an alternative approach, particularly for those unable to participate in aerobic training. The effect of RT on muscle strength is mainly during slow controlled movements and not during rapid movements. Older adults and patients with advanced CHF are underrepresented in RT trials and future studies should seek to optimise their inclusion.

Homoarginine and 3-nitrotyrosine in patients with takotsubo cardiomyopathy

In recent years, homoargininewas shown to be a cardiovascular risk factor [1], and to herald a poor prognosis in heart failure patients [2]. Yet, the underlying mechanism is elusive. Human and animal studies suggest that the enzyme responsible for the biosynthesis of homoarginine is arginine:glycine amidinotransferase (AGAT) [3–5]. Previously, excessive myocardial AGATgene expressionwas observed in heart failure; the authors implicated AGAT in cardiac creatine synthesis [6]. This finding suggests that homoarginine synthesis in the myocardiummay be elevated in heart failure. Thus far, there is no information about the homoarginine homeostasis in takotsubo cardiomyopathy (TTC) and which potential role this quite neglected non-proteinogenic amino acid may play in the development and recovery of TTC. In TTC patients we recently observed that the plasma concentration of asymmetric dimethylarginine (ADMA), another arginine homologue, is lower than the control, whereas the responsiveness to nitric oxide (NO) is substantially greater compared to healthy females [7]. This is of particular interest, because both L-arginine and L-homoarginine serve as substrates for NO synthases (NOS), while ADMA inhibits NOScatalyzed production of NO from these substrates [8]. The aim of the present study was to measure plasma homoarginine concentration inTTC patients and healthy controls of a previous study [7] and to determine its relationship to 3-nitrotyrosine, a biomarker of NO-related oxidative stress. Plasma homoarginine and 3nitrotyrosine were measured by validated, previously reported gas chromatography-tandem mass spectrometry (GC-MS/MS) methodologies [9,10]. Written informed consent was provided by all subjects included in the study, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the local Ethics Committee of the Central Northern Adelaide Health Service: the Queen Elizabeth Hospital and Lyell McEwin Hospital (protocol number, 009014). The plasma concentration of homoarginine was significantly reduced in TTC patients compared to healthy controls (mean ± SEM; 1298 ± 112 nmol/L vs. 2094 ± 321 nmol/L; median 1403 nmol/L vs. 1634 nmol/L) (Fig. 1A). 3-Nitrotyrosine plasma concentrations were similar in TTC patients and in healthy controls (mean ± SEM; 2355 ± 217 pmol/L vs. 2227 ± 146 pmol/L; median 1915 pmol/L vs. 2170 pmol/L) (Fig. 1B). Pearson correlation between homoarginine and 3-nitrotyrosine concentrations revealed a significant negative relationship in TTC patients (Fig. 2A). In contrast, a positive relationship was observed in the control group (Fig. 2B). No relationship was obtained when all homoarginine and 3-nitrotyrosine data from TTC patients and controls were correlated (not shown). In the TTC patients, plasma homoarginine concentration correlated inversely with systolic blood pressure (SBP) (Fig. 2C). It is worth mentioning that plasma homoarginine concentrationwas found to correlate positively with SBP in an elderly population (50–87 years) non-suffering from takotsubo cardiomyopathy [11]. In contrast, plasma 3-nitrotyrosine concentration did not correlate with SBP (Fig. 2C). Our study indicates that plasma homoarginine concentrations are reduced in TTC patients. They are considerably lower than those measured by us and others in healthy subjects [1–5]. With the exception of four TTC patients, the plasma concentrations of 3nitrotyrosine measured in the other TTC patients and in the control subjects are comparable with those reported in the literature for healthy and ill subjects. The limited number of TTC patients and healthy controls investigated in our study limits the power of our findings. Nevertheless, the results of the present study in TTC supports recent studies indicating homoarginine as a novel marker of cardiovascular disease [1–5]. In contrast to elderly males and females with normal or impaired glucose metabolism or with type 2 diabetes mellitus but without TTC [11], in our TTC patients there was a negative correlation

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.