Malcolm Walker

Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations

Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia–reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the “Hatter Workshop Recommendations”. These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit.

Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop

The 7th biennial Hatter Cardiovascular Institute Workshop, comprising 21 leading basic science and clinical experts, was held in South Africa in August 2012 to discuss the current cutting edge status of cardioprotection and the application of cardioprotective modalities in the clinical management of myocardial ischaemia/reperfusion injury in the context of acute coronary syndromes and cardiac surgery. The meeting, chaired by Professor Derek Yellon and Professor Lionel Opie, was run to a format of previous Hatter Cardiovascular workshops with data presented by proponents followed by discussion and debate by the faculty.

Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload

To explore the use and reproducibility of magnetic resonance‐derived myocardial T1 mapping in patients with iron overload.

From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research"

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.

Worldwide survey of T2* cardiovascular magnetic resonance in Thalassaemia

Results Overall, 57.5% of patients had no significant iron loading (T2* >20ms), 22.6% had moderate cardiac iron (10ms 50%) in South-East Asia had cardiac iron (T2* >20ms) at baseline. At the time of the first scan, 100 patients (3.3%) had confirmed heart failure, the majority of whom (77.0%) had myocardial T2* <10ms with almost all (99%) having T2* <20ms. There were 113 patients who subsequently developed heart failure. 92.0% of these had T2* <10ms and 99.1% had a T2* <20ms. There were 39 deaths. Cardiac T2* values were <10ms in 79.5%, with 92.3% <20ms. Conclusions Even in this well-treated cohort with access to transfusion, chelation and CMR, there is a large proportion of TM patients with moderate to severe cardiac iron loading. Low T2* (<10ms) is associated with cardiac failure and death. There is a huge unmet worldwide need in terms of access to specialist medical care (including transfusion and chelation therapy) together with advanced monitoring techniques (such as CMR).

Superior Vena Cava Occlusion by Cardiovascular Magnetic Resonance

A 30-year-old man was referred for cardiac and hepatic iron quantification by cardiovascular magnetic resonance. He was known to have β-thalassemia major and was heavily transfusion dependent, requiring intensive intravenous chelation therapy. However, after nonadherence to anticoagulation and parenteral therapy, his Portacath had thrombosed, necessitating removal. Cardiovascular magnetic …

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.

A NOVEL NON-INVASIVE METHOD OF ASSESSING CARDIOVASCULAR FUNCTION USING MAGNETIC RESONANCE AUGMENTED CARDIOPULMONARY EXERCISE TESTING

Background: Reduced exercise capacity is a common feature of many cardiovascular diseases. Quantitative assessment of exercise capacity is usually achieved by conventional CPET measuring peak oxygen consumption (VO2). However this neglects different components of reduced exercise capacity namely reduced cardiac output (CO) and oxygen extraction (ΔcO2). This study aims to demonstrate a comprehensive approach to simultaneously measure VO2 and CO and then calculate ΔcO2.

135 Cardiovascular Complications in Sickle Cell Disease

Introduction Sickle cell disease (SCD) is a genetic disorder affecting the production of haemoglobin (Hb). It has life-long consequences with multi-organ involvement including the cardiopulmonary circulation and an increased mortality. Although all SCD patients share the same genetic defect, the phenotype varies. This suggests other factors, unrelated to the Hb mutation, play an important role particularly in later decades. This retrospective study examined patient survival attending a specialist tertiary centre in the United Kingdom based on Tricuspid Regurgitant Jet Velocity (TRJ) measured by echocardiography and associated laboratory studies. Method A retrospective analysis of TRJ and diastolic function (lateral E/E’ ratio) assessed by echocardiography in 127 intensively treated steady-state SCD patients (mean age 40 +/- 12 years) screened for cardiovascular complications. Laboratory studies were also analysed. Results The clinical characteristics of patients in this study is summarised in Table 1. 15% of patients had a TRJ between 2.6–2.99 m/s and 9% with TRJ >3.0 m/s. 11% of patients had diastolic dysfunction using lateral E/E’ ratio. Abstract 135 Table 1 Clinical characteristics of SCD patients Variable Number Summary Male gender – n (%) 127 50 (39%) Age – mean (SD) 127 40 (12) TRJ – mean (SD) 127 1.6 (1.1) Haemoglobin (g/l) – mean (SD) 127 9.0 (1.5) Reticulocyte (%) – median (IQR) 127 7 (4.41, 10.13) Ejection Fraction (%) – mean (SD) 127 63 (9) Lateral E/E’ ratio – mean (SD) 127 7.79 (3.27) Transfusion – n (%) 127 45 (35%) Hydoxycarbamide – n (%) 127 41 (32%) When compared to patients with a TRJ <2.5 m/s, the risk of death is 4 times higher in the 2.6–2.99 TRJ group and 24 times higher in the > 3.0 TRJ group. See Figure 1. Abstract 135 Figure 1 Kaplan-Meier survival curves for SCD patients arranged according to TRJ range Lateral E/E’ ratio (beta = 0.88, p = 0.015), left atrial area (beta = 0.38, p < 0.001) and microalbuminuria (beta = 0.10, p = 0.05) were independently associated with TRJ. Conclusion Mortality in SCD patients with raised TRJ remains high despite intensive therapy, such as exchange transfusion, directed at correcting Hb. Screening with echocardiography remains an important tool in identifying high-risk patients. Additional therapies directed at the premature ageing of the cardiopulmonary circulation are urgently needed.

134 MR Augmented Cardiopulmonary Exercise Testing – a Novel Way of Assessing Cardiovascular Function

Introduction Reduced exercise capacity is a common feature of many cardiovascular diseases. Quantitative assessment of exercise capacity is usually achieved by measuring peak oxygen consumption (VO2). However, measuring peak VO2 alone neglects the different components of reduced exercise capacity: namely reduced cardiac output (CO) and oxygen extraction (ΔcO2). A better approach would be to simultaneously measure VO2 and CO and then calculate ΔcO2. This could be achieved using MR augmented cardiopulmonary exercise testing (MR-CPET). The aims of this study were to demonstrate: 1) MR-CPET is feasible and well tolerated, 2) peak VO2 in the MR scanner correlates with conventional peak VO2 and 3) variation in peak VO2 is related to both peak CO and peak oxygen extraction (ΔcO2) as calculated by the Fick equation. Method 17 healthy volunteers (21–55 years) underwent MR-CPET. Exercise was performed on an MR-compatible ergometer (Lode, Groningen, The Netherlands) and VO2 was assessed using a commercial respiratory gas analyser (Ultima, MedGraphics, St. Paul, USA) with a modified sampling tube that was MR compatible. Set-up for MR-CPET is shown in Figure 1. Aortic flow was continuously measured using a previously validated UNFOLD-SENSE spiral PCMR sequence. Images were reconstructed using a graphical processing unit card and analysed using an in-house plug-in for OsiriX software. Conventional CPET was also performed within 2 weeks of MR-CPET. For both tests, participants were asked to rate i) concern ii) comfort and iii) perceived helplessness. Abstract 134 Figure 1 Set-up for MR-CPET: a) subject in exercise position on MR compatible ergometer b) subject with facemask attached to MR compatible umbilicus passing through the wave-guide Results 15 out of 17 volunteers completed exercise; exclusions were due to claustrophobia (n = 1) and inability to master exercise technique (n = 1). Reported concern and discomfort was higher with MR-CPET, although still within acceptable limits. Peak VO2, peak VCO2 and VE showed strong correlation between conventional CPET and MR-CPET: VO2 peak (r = 0.94, p < 0.001); VCO2 (r = 0.87, p < 0.001); VE (r = 0.88, p < 0.001). Resting and peak values VO2, CO, HR, SV and ΔcO2 are shown in Table 1. Multiple linear regression analysis demonstrated that both peak CO and ΔcO2 were independent predictors of peak VO2 measured during MR-CPET (beta = 0.73 and 0.38 respectively, p < 0.001) and conventional CPET (beta = 0.78 and 0.28 respectively, p < 0.001). Abstract 134 Table 1 Values at rest and Peak VO2 obtained at MR-CPET Conclusion MR-CPET is feasible, well tolerated and demonstrates physiology not apparent with conventional CPET. In this study, we have shown that MR-CPET allows assessment of the differing contributions of CO and ΔcO2 to variation in peak VO2. We believe that will be useful in understanding the origin of reduced exercise capacity in cardiac disease.