Nishat Siddiqi

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.

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.

Cardiac metabolism in hypertrophy and heart failure: implications for therapy

The heart consumes huge amounts of energy to fulfil its function as a relentless pump. A highly sophisticated system of energy generation based on flexibility of substrate use and efficient energy production, effective energy sensing and energy transfer ensures function of the healthy heart across a range of physiological situations. In left ventricular hypertrophy and heart failure, these processes become disturbed, leading as will be discussed to impaired cardiac energetic status and to further impairment of cardiac function. These metabolic disturbances form a potential target for therapy.

Protocol: does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI)

BackgroundWhilst advances in reperfusion therapies have reduced early mortality from acute myocardial infarction, heart failure remains a common complication, and may develop very early or long after the acute event. Reperfusion itself leads to further tissue damage, a process described as ischaemia-reperfusion-injury (IRI), which contributes up to 50% of the final infarct size. In experimental models nitrite administration potently protects against IRI in several organs, including the heart. In the current study we investigate whether intravenous sodium nitrite administration immediately prior to percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction will reduce myocardial infarct size. This is a phase II, randomised, placebo-controlled, double-blinded and multicentre trial.Methods and outcomesThe aim of this trial is to determine whether a 5 minute systemic injection of sodium nitrite, administered immediately before opening of the infarct related artery, results in significant reduction of IRI in patients with first acute ST elevation myocardial infarction (MI). The primary clinical end point is the difference in infarct size between sodium nitrite and placebo groups measured using cardiovascular magnetic resonance imaging (CMR) performed at 6–8 days following the AMI and corrected for area at risk (AAR) using the endocardial surface area technique. Secondary end points include (i) plasma creatine kinase and Troponin I measured in blood samples taken pre-injection of the study medication and over the following 72 hours; (ii) infarct size at six months; (iii) Infarct size corrected for AAR measured at 6–8 days using T2 weighted triple inversion recovery (T2-W SPAIR or STIR) CMR imaging; (iv) Left ventricular (LV) ejection fraction measured by CMR at 6–8 days and six months following injection of the study medication; and (v) LV end systolic volume index at 6–8 days and six months.Funding, ethics and regulatory approvalsThis study is funded by a grant from the UK Medical Research Council. This protocol is approved by the Scotland A Research Ethics Committee and has also received clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number: 2010-023571-26).Trial registrationClinicalTrials.gov: NCT01388504 and Current Controlled Trials: ISRCTN57596739

T1 mapping for assessment of myocardial injury and microvascular obstruction at one week post myocardial infarction

OBJECTIVES To compare 3T T1 mapping to conventional T2-weighted (T2W) imaging for delineating myocardial oedema one week after ST-elevation myocardial infarction (STEMI), and to explore the confounding effects of microvascular obstruction (MVO) on each technique. METHODS T2W spectral attenuated inversion recovery and native T1 mapping were applied in 10 healthy volunteers and 62 STEMI patients, and late gadolinium enhancement was included for infarct localisation at 1 week and at 6 months post-STEMI. Segmental T1 values and T2W signal intensity ratios were calculated; oedema volumes and salvage indices were determined in patients using image thresholding-a receiver operator characteristic (ROC) derived T1 threshold, and a 2SD T2W threshold; and the results were compared between patients with/without MVO (n=35/27). RESULTS Native T1 mapping delineated oedema with significantly better discriminatory power than T2W-as indicated by ROC analysis (area-under-the-curve, AUC=0.89 versus 0.83, p=0.009; and sensitivity/specificity=83/83% versus 73/73%). The optimal ROC threshold derived for T1 mapping was 1241ms, which gave significantly larger oedema volumes than 2SD T2W (p=0.006); with this threshold, patients with and without MVO showed similar oedema volumes, but patients with MVO had significantly poorer salvage indices (p<0.05) than those without. Neither method was significantly affected by MVO, the volume of which was seen to increase exponentially with infarct size. CONCLUSIONS Native T1 mapping at 3T can delineate oedema one week post-STEMI, showing larger oedema volumes and better discriminatory power than T2W imaging, and it is suitable for quantitative thresholding. Both techniques are robust against MVO-related magnetic susceptibility.

The impact of methodological and temporal variation on infarct size quantification in acute myocardial infarction with late enhancement CMR

Methods 55 patients with reperfused, first acute ST-elevation AMI underwent LGE-CMR on a Philips Achieva 3T scanner at 1 week and 6 months post AMI. IS was expressed as a percentage of LV volume and measured at both time points using: manual planimetry, signal intensity threshold indicating LGE set at 2, 3 and 5 standard deviations (SD) above the remote myocardium and the full width at half maximum (FWHM) technique, which uses half the maximal signal within the scar as the threshold. The relationship between all measures of IS and final (6 month) LV ejection fraction (LV EF) and LV end diastolic volume (LV EDV) was evaluated using Spearman correlations.

MOLLI T1 mapping versus T2 W-SPAIR at 3T: myocardial area at risk measurements and the influence of microvascular obstruction

Background Robust CMR imaging is required for the delineation of myocardial area at risk (AAR), so that the success of reperfusion therapies can be evaluated. In this work, we investigate the performance of T1 mapping in assessing AAR one week post-STEMI, and explore the effect of microvascular obstruction (MVO) on T1 relaxation times. Methods CMR imaging was conducted on a Philips 3T Achieva MRI scanner. T2W-weighted spectral attenuated inversion recovery (T2WW-SPAIR), modified look-locker inversion recovery (MOLLI) T1 mapping and late gadolinium enhancement (LGE) sequences were applied as short axis stacks in 10 healthy volunteers and 62 STEMI patients. Receiver operator characteristic (ROC) analysis was applied to calculate a cut-off T1 to to discriminate AAR from normal myocardium. The presence of LGE was used as the positive ROC test state, while healthy myocardium, as measured in volunteers, was used as the negative ROC test state. For comparison with T1 mapping, the AAR was also measured on T2WW images using a threshold signal intensity > 2SD greater than remote. The derived myocardial edema volumes and salvage indices were compared between MVO+ and MVO- groups. Results For T1 mapping, ROC analysis gave a significantly larger area-under-the-curve (AUC) as compared to T2WWSPAIR for delineating myocardial edema (AUC = 0.89

The need for speed? Examples from a randomised controlled trial in the emergency setting

There are a number of unique challenges associated with setting-up and running randomised controlled trials in an emergency setting. Within the NIAMI (Nitrates in Acute Myocardial Infarction) Trial patients present as an emergency and clinicians aim to start primary percutaneous coronary intervention (PPCI) without unnecessary delay. The trial drug is delivered before PPCI is commenced - so there is some urgency to assess the patients eligibility, gain agreement from the patient to take part in the trial and deliver the trial drug. To minimise any delay in commencing PPCI, we designed the study so that the inclusion and exclusion criteria are simple and quick to assess, patients are given a short verbal explanation of the study and give verbal agreement if they wish to take part (we seek fully informed consent 6-48 hours later), and the study drug packs are pre-randomised and stored in the facility where PPCI is undertaken (to minimise any delay in using telephone or web-based randomisation and collecting the study drug from Clinical Trials Pharmacy). To meet recruitment targets, 24-hour recruitment was implemented - this relied on the goodwill and buy-in from the entire clinical team (and not just from the immediate trial team who were often not present out-of-hours). Overcoming these challenges at the design and implementation phases of the trial has contributed to it reaching recruitment targets. Drawing on our experience from NIAMI, we will discuss some of the challenges, and how these were overcome.