Heart Research Wales 

Historically, the rate of suffering a life threatening blood clot, after heart valve replacement has been 2-4% per year. As a potentially avoidable complication of the procedure, it is imperative that all of the risk factors contributing to the formation of these blood clots, are identified. This will allow us to recognise those at a higher risk, and monitor them more vigilantly.

 

The Cardiff Embolic Risk Factor Study (CERFS), was designed to determine what risk factors were most influential in the formation of blood clots, in patients with prosthetic heart valves.

 

With help from the Heart Research Wales Charity, the study recruited 370 individuals who were undergoing lifesaving surgery, for the insertion of a prosthetic heart valve. Using laboratory tests and echocardiography (heart imaging), the individuals were assessed before, after and 15 years after their operation, to monitor their risk factors, and their outcome. Some of the risk factors investigated included, the type of valve they had inserted, whether they were compliant with their blood thinning medication and how well their heart was working.

 

The studies hypothesis was confirmed: there were certain factors that contributed to an increased incidence of blood clots. Including infection with Chlamydia Pneumoniae, hypertension, diabetes, and pro-clotting disorders.

 

The study also found an increased frequency in the number of blood clots, in patients with a specific type of prosthetic valve, called "Silzone". As a consequence of this finding, the valve has been removed from the market. 

 

This is a fantastic result, which will surely improve the care of patients with prosthetic heart valves in the future. Well one Professor Fraser and team!

Metal-on-metal hip prostheses were developed to be durable and to have a low risk of serious side effects, and they have been used by orthopaedic surgeons for many decades. After changes to the design of some metal-on-metal hips, however, a small number of patients developed progressive local tissue reactions leading to soft tissue necrosis.  In 2010, the National Joint Registry (NJR) in the UK identified higher than expected revision rates for metal-on-metal implants, and the Medicines and Healthcare products Regulatory Agency/ MHRA (an executive agency of the Department of Health) issued a Medical Device Alert and guidance to orthopaedic surgeons that the devices should no longer be implanted. It issued further guidance in 2012 that patients should have annual follow-up and revision surgery if they experience any adverse local joint and tissue effects.

 

There have been some isolated reports in the medical literature, and we have had some limited local experience, of patients with metal-on-metal hip replacements who have developed heart muscle dysfunction.  Extensive investigations have often failed to identify any known cause. Some patients have had high concentrations of heavy metal ions (cobalt and chromium).

 

We are studying patients with metal-on-metal hip replacements to measure the levels of cobalt and chromium in their blood, and to study their heart function with detailed echocardiography. Other tests that we are performing include measurements of heart rhythm, lung function, and thyroid, kidney and liver function. The results will allow us to determine if heart function is related to blood levels of cobalt and chromium, or if the patients who have experienced heart problems must have had another cause for their symptoms.

 

With help from the Heart Research Fund for Wales, this study has already recruited about 100 individuals, including patients with metal-on-metal hips and some control subjects who received other types of joints. Our study is the largest and most detailed study of heart function in such patients and therefore the results should be able to guide health care professionals about whether or not these prosthetic implants should be revised even if there are no local tissue effects.

 

Left ventricular (LV) function is an important predictor of outcome after cardiac surgery.  Severely impaired LV function (EF<20%) carries a 4-fold increase in the risk of in-hospital mortality v EF >40%.  

 

Optimising LV function in the peri-operative setting may improve outcomes.  Haemodynamic studies of permanent BiV pacing have reported a relative 25% increase in EF compared to dual-chamber right ventricular pacing.

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The median duration of level 3 care was 22.0 (IQR: 16.0-66.5) hours and 37.5 (IQR: 16.3-55.0) hours in the BiV and standard pacing groups respectively (log-rank p=0.58, 95% CI: 0.43-1.61).  

At 18 hours, cardiac output with biventricular pacing (5.8 L/min) was 9% higher than dual chamber right ventricular pacing (5.3 L/min), ( p=0.001).  Optimisation of the VV interval produced a further 4% increase in cardiac output (p=0.005).     

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Analysis of the cardiac output measurements taken simultaneously from the PA catheter and FloTrac system yielded a bias -0.33L/min±2.2 L/min and a percentage error of 42%.  

 

Patients who require post-operative pacing or a prolonged haemodynamic support after surgery may benefit from optimised BiV pacing.  However, for the majority of patients BiV pacing does not alter the clinical outcome compared to atrial-only or dual chamber RV pacing.

Although the FloTrac system is easy to use and rapidly reports changes in cardiac output, its precision requires refinement before it can be used instead of a PA catheter.

The generous support from Heart Research Fund for Wales enabled me to travel and attend the most important European meeting in Cardiovascular Imaging in 2013, the EuroEcho 2013. This congress took place in Istanbul, Turkey.

 

 I presented the initial results of our multi-centre, European study (MEDIA: The Metabolic Road to Diastolic Heart Failure)

Heart failure (HF) is becoming more common in Europe as the population ages. More than 50% of HF patients have normal global left ventricular (LV) systolic function and so they are presumed to have heart failure with preserved ejection fraction (HFPEF). Many older patients in the community with unexplained breathlessness on exertion may have DHF, especially if they have hypertension or diabetes mellitus.

 

In the Wales Heart Research Institute (Cardiff) we were investigating patients with HFPEF compared with breathless control subjects, hypertensive controls and healthy controls. The aims of were to assess interactions between arterial stiffness and LV diastolic function and to refine the diagnostic strategy for DHF. We were measuring arterial function at rest, and changes in diastolic LV function from rest to exercise using tissue Doppler and speckle tracking echocardiography during semi-supine bicycle stress. The diagnostic utility of these tests are compared against assays of serum N-terminal-pro-brain-natriuretic peptide.

 

The title of my presentation at EuroEcho was “Which indices demonstrate changes in diastolic function during sub-maximal exercise testing?”. Our results suggested, that early diastolic myocardial velocity (e’) and flow propagation velocity (Vp) demonstrate impaired diastolic functional reserve in HFPEF, possibly related to delayed untwisting and reduced suction. Although E/e’ (a controversial marker of LV filling pressure) is a criterion that is recommended for diagnosing HFPEF, in these subjects it demonstrated changes during submaximal exercise that were opposite to those expected, raising doubts about its utility for discriminating patients with HFPEF

The effects of preload reduction on diastolic flow, short and long axis function have been previously studied. However its effect on left ventricle (LV) rotation and torsion is not known. LV rotation and torsion contribute significantly to overall LV function and can be assessed non-invasively with 2 dimensional speckled tracking on standard echocardiography short axis images.

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We modelled the effect of preload reduction on LV rotational mechanics following a single session of haemodialysis.

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Majority of subjects had hypertension (93%, blood pressure 131±25/68±16mmHg), some had diabetes mellitus (30%) and mild ischaemic heart disease (13%, CCS class I). Causes of renal failure were: hypertension (63%), obstructive uropathy (27%) and diabetes mellitus (20%).

 

The median weight loss following dialysis was 1.6±1.3kg (95% CI 1.1-2.1, p<0.001). LV torsion was calculated as the difference in apical and basal rotation, corrected for LV length (degree/cm).

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Preload reduction resulted in increased apical rotation and overall LV torsion, despite unchanged early untwisting and peak untwisting rate. These findings suggest unchanged intrinsic myocardial properties despite a positive inotropic response. Loading condition should be considered when assessing LV torsion.

Preload reduction during haemodialysis causes change in cardiac filling and contractile function. This can be accurately assessed using standard echocardiography(ECHO). We hypothesise that simple ECG parameters approximate ECHO derived measurements and can be used as an initial tool.

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The median weight loss following dialysis was 1.6±1.3kg (95% CI 1.1-2.1, p<0.001). Average basal septal and lateral systolic velocity increased by 1.1±2.3 cm/s (95% CI 0.1-2.1, p=0.03) and this is reflected in the increase of sum and average QRS amplitude by 19±31mm (95% CI 7-31, p<0.01) and 1±1mm (95% CI 0.8-1.8, p<0.001). Diastolic filling pressure was reduced, E/A dropped by 0.15±0.28 (95% CI 0.03-0.26, p=0.01) and Tend P/PQ showed a small but non significant drop by 0.2±0.6 (95% CI 0-0.4, p=0.10) despite no change in heart rate.

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Preload reduction resulted in increased contractile function despite reduced filling pressure. ECG QRS voltage amplitude is preload dependent and relatively simple to measure. This approximates the change in Sm and can be used for initial assessment.

Preload reduction during haemodialysis causes change in cardiac filling and contractile function. This can be accurately assessed using standard echocardiography(ECHO). We hypothesise that simple ECG parameters approximate ECHO derived measurements and can be used as an initial tool.

​

The median weight loss following dialysis was 1.6±1.3kg (95% CI 1.1-2.1, p<0.001). Average basal septal and lateral systolic velocity increased by 1.1±2.3 cm/s (95% CI 0.1-2.1, p=0.03) and this is reflected in the increase of sum and average QRS amplitude by 19±31mm (95% CI 7-31, p<0.01) and 1±1mm (95% CI 0.8-1.8, p<0.001). Diastolic filling pressure was reduced, E/A dropped by 0.15±0.28 (95% CI 0.03-0.26, p=0.01) and Tend P/PQ showed a small but non significant drop by 0.2±0.6 (95% CI 0-0.4, p=0.10) despite no change in heart rate.

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Preload reduction resulted in increased contractile function despite reduced filling pressure. ECG QRS voltage amplitude is preload dependent and relatively simple to measure. This approximates the change in Sm and can be used for initial assessment.

Familial Hypercholesterolaemia (FH) is a genetic condition that leads to high cholesterol levels in the bloodstream.   It can lead to early onset coronary heart disease if not detected and treated.  If diagnosed early and cholesterol levels controlled with medication, individuals can expect to have a normal life expectancy. 

 

Genetic Variants in FH- Why they are Important

FH is caused by variants in the genes that control the way the body handles cholesterol, specifically “low density lipoprotein cholesterol”.  Some variants in these genes can cause disease (these are called pathogenic), some variants do not cause disease (non-pathogenic), and for others it is not clear if they cause disease or not (variants of uncertain significance (VUS)).

 

Finding a pathogenic variant for FH makes a clear diagnosis for that individual and allows the right treatment to be given.  Also it means that other members of their family can be offered a test for the same genetic variant so that they can get early diagnosis and treatment and avoid early heart attacks.

On the other hand if a genetic variant is shown to be “non-pathogenic” then this individual and family can be advised that this genetic variant is not important which is reassuring and avoids unnecessary investigations.

 

Therefore it is important to try and find out if variants of uncertain significance are pathogenic or not.

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The Wales FH service has been running since December 2010 to provide genetic testing for some patients attending lipid clinics across Wales.  Further information is available on www.fhwales.co.uk

In 9% of these patients who have genetic testing a variant of uncertain significance (VUS) has been found.

 

This Research Project and Preliminary Results

This research is a joint project with the NHS Wales FH Service, Cardiff University and the Heart Research Fund for Wales

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The study aims to assess whether or not the VUS tracks with raised cholesterol in families.  This involves contacting family members to ask for their consent to be involved.  Blood is taken for cholesterol measurement and genetic testing for the VUS.

 

Specialist genetic association statistical analysis is used to quantify the likelihood of pathogenicity based on the family relationship, number of subjects, and LDL-Cholesterol (with adjustment for age and gender).  Data from families who share the same VUS can be combined. The degree of association is statistically quantified as significant or not using a probability (p)-value).  This evidence can be used by the diagnostic laboratory to help to make decisions about whether or not the variant is disease-causing (pathogenic).

Data from 126 family members from 34 families has been collected to date and statistical analysis has been completed on 14 of these families (9 different VUS). Based on this analysis the All Wales Medical Genetics Service has successfully re-classified most of these as either pathogenic or non-pathogenic variants.

Heart Research, Wales has given me the opportunity to present my abstract in the European Society of Cardiology Conference 2013 in Amsterdam. It was an extraordinary and unique experience for my educational and professional development in medicine. I am truly indebted to the Heart Research, Wales.

 

The topic of my presentation was the status of primary prevention of Cardiovascular Disease in the United Kingdom, focusing solely in the management of lipids and blood pressure. The talk delivered a strong message to the global medical community, in that both risk factors are not being optimally managed in the primary prevention setting at the moment but this could be considerably improved with stronger adherence to British and/or European guideline recommendations.

 

Overall, the talk was a great success indeed. Attendance surpassed the capacity of the venue, which must had been able to accommodate approximately 200 delegates, so that many attendees were standing on the side or by the entrance. An engaging discussion followed from the floor regarding adherence to guideline recommendations.

 

Preparing and delivering the presentation aimed at an expert audience enabled me to improve my knowledge in Cardiology as well as in my abilities for medical and scientific debate. Furthermore, the very variable events in the congress provided me with excellent educational opportunities of the most up-to-date knowledge in my field of interest. In addition, not necessarily related to my presentation only, this experience was a great opportunity for networking in the field of Cardiology and research that I hope it will prove invaluable in the future.

 

I am very grateful for your important economical support and for allowing all of the above to take place.