Cardiovascular - Recent Highlights

Hypertension and vascular inflammation

In patients with hypertension we (Brown) have identified that up to 10% of hypertension patients possess small adrenal aldosterone-producing adenomas (APAs, or Conn’s adenomas) that would be missed by conventional CT/MRI scanning.

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In patients with hypertension we (Brown) have identified that up to 10% of hypertension patients possess small adrenal aldosterone-producing adenomas (APAs, or Conn’s adenomas) that would be missed by conventional CT/MRI scanning. These patients are defined by the presence of novel somatic mutations in ATP1A1 and CACNA1D in the zona glomerulosa (Azizan et al. Nat Gen. 2013). Increased aldosterone production is linked to increased Wnt signalling in the adenomas. We have shown that these APAs can be detected by (11)C-metomidate positron emission tomography (PET)-CT, raising the possibility of early ablation in these patients. Patients with COPD have increased cardiovascular risk, over and above that explained by traditional risk factors such as smoking and blood pressure. Chronic inflammation from the lungs presents a novel therapeutic target. The ERICA programme, jointly funded by the Technology Strategy Board and GSK, is co-led by Ian Wilkinson and run by the Cambridge CTU (700 patients recruited). The main aims are to determine the prognostic value of inflammatory biomarkers, and to evaluate the impact of two novel anti-inflammatory compounds (p38MAPkinase inhibitor [losmapimod] and a soluble epoxide hydrolase inhibitor) (Elkhawad et al. JACC Cardiovasc Imaging. 2012) on vascular inflammation and function in COPD using a stratified medicine approach (Wilkinson/Cheriyan).


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Pulmonary hypertension

We have identified novel biomarkers of prognosis/survival in patients with pulmonary arterial hypertension (PAH) (interleukins and TNF-a) and have demonstrated a novel role for Natural Killer cells in disease pathobiology (Ormiston et al Circulation 2012).

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We have identified novel biomarkers of prognosis/survival in patients with pulmonary arterial hypertension (PAH) (interleukins and TNF-a) and have demonstrated a novel role for Natural Killer cells in disease pathobiology (Ormiston et al Circulation 2012). We have provided proof-of-concept for targeting the BMPR2 pathway, mutations in which represent the commonest genetic form of PAH. This is revealing stratified approaches to target BMPR2 based on the underlying mutation (Dunmore et al Hum Mol Genetics 2013). For example, in preclinical studies and human cells we have shown that hydroxychloroquine improves BMPR2 signalling (by inhibiting lysosomal degradation), inhibits autophagy, and reverses experimental PAH (Long et al Circ Res 2013). We (Morrell) have established of a UK-wide network to establish the genetic architecture of idiopathic and familial PAH by whole genome sequencing, and to study the epidemiology (with Danesh), and provide a platform for biomarker and experimental medicine studies. We have generated and validated the first iPSC model of heritable PAH by generating endothelial cells, smooth muscle cells and cardiomyocytes from BMPR2 mutation carriers.

March 2014


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Heart failure

Research in heart failure comprises of two areas related to left ventricular performance.

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Research in heart failure comprises of two areas related to left ventricular performance. Firstly, we have taken the concept of using GLP-1 to protect the heart during ischaemia from initial proof-of-concept studies to small Randomised Control Trial (RCT) to a position where the results are underpinning a larger RCT during percutaneous coronary intervention. The second area of research addresses the optimum use of cardiac resynchronisation therapy (CRT) in those with advanced heart failure. An RCT supported by the BRC at Papworth and CUHFT demonstrated the importance of LV lead position and other factors such as scar burden (Kahn et al JACC 2012). This research has informed the latest CRT guidelines in the US. The BRC has also enabled experimental medicine studies to assess the utility of GLP-1 to protect the heart against stunning and ischaemic LV dysfunction (McCormick et al. Circ Cardiovasc Imaging 2014)

March 2014


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Population genetics in cardiovascular disease

The group aims to address inter-related questions of translational relevance in the large scale genetic studies of cardiovascular disease.

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What is the clinical value of assessing established and emerging biomarkers in the prediction of first-onset cardiovascular disease?

In detailed analyses of the 2.5 million-person Emerging Risk Factors Collaboration, we have informed international guidelines by showing that there is little incremental prediction provided by assessment of C-reactive protein (NEJM 2012), lipoproteins (JAMA 2012), glycated haemoglobin (JAMA 2014), or fatty acids (Ann Int Med 2014). We have helped to show that lipoprotein(a) is a causal risk factor for aortic valve calcification (NEJM 2013).

Can large-scale human genetic and biomarker studies help to validate (or invalidate) novel therapeutic targets?

We have led, or contributed to, studies that validate interleukin-6 signalling as a target in coronary disease (Lancet 2012; PLoS Genet 2013) and argued against causality for plasma homocysteine in coronary disease (PLoS Med 2012).

What are risk factors for cardiometabolic diseases in South Asians?

In our case-control studies based in Pakistan and Bangladesh that have recruited >40,000 participants, we have helped to identify a novel locus that contributes to type 2 diabetes susceptibility in Sikhs of Punjabi origin, but not in other South Asians or in global populations (Diabetes 2013). We have led, or contributed to, consortia that have identified new risk loci for coronary disease (Nat Genet 2012a) and type 2 diabetes (Nat Genet 2012b).

March 2014


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Scientists develop new technique that could improve heart attack prediction

Building on work pioneered in Cambridge 10 years ago, scientists have developed a new imaging approach that could help improve how doctors predict a patient’s risk of having a heart attack.

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First use of PET and CT to look at disease processes leading to heart attack

The British Heart Foundation (BHF) funded project, a collaboration between scientists from the Universities of Cambridge and Edinburgh, is the first to demonstrate the potential of combined PET and CT imaging to highlight the disease processes causing heart attacks directly within the coronary arteries.

The research, published recently in the Journal of the American College of Cardiology (JACC), involved imaging over 100 people with a CT calcium scan to measure the amount of calcified or hardened plaques in their coronary arteries. This is a standard test, which is commonly used to predict heart attack risk but cannot distinguish calcium that has been there for some time from calcium that is actively building up.

The patients were also injected with two contrast agents that show up on PET imaging scans, and which can be used to track various metabolic pathways in the body. One of these tracers, 18F-sodium fluoride (18F-NaF), is a molecule taken up by cells in which active calcification is occurring. The 18F-NaFcan then be visualised and quantified during a PET scan.

The researchers wanted to see if they could identify patients with active, ongoing calcification because these patients may be at higher risk of heart attack than patients in whom the calcium developed a long time ago. The results showed that increased 18F-NaF activity could be observed in specific coronary artery plaques in patients who had many other high-risk markers of cardiovascular disease.

Dr James Rudd, HEFCE Senior Lecturer at the Department of Medicine and joint senior author of the paper, said:

'Our results show, for the first time, that certain areas of atherosclerosis within the coronary arteries, previously thought to be inert, are actually highly active and have the potential to cause heart attack. Once identified, they might be targeted with drug therapy more effectively.

'Additionally, we might be able to improve our ability to predict an individual person's future risk of heart attack using this fairly straightforward imaging test in selected people.

'This research exploits longstanding scientific links between my research team in Cambridge and Professor Newby's in Edinburgh, with core support from the Cambridge NIHR Biomedical Research Centre, HEFCE and the British Heart Foundation.'


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