Non-invasive Coronary Physiological Reserve to Determine the Physiological Significance of Aortic Stenosis

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Aortic stenosis is the most common valve defect of the heart and causes chest pain, breathlessness and sudden death. Currently, patients are monitored until they develop symptoms on exertion before replacing the valve. If valve replacement is too late, irreversible damage to the heart muscle can occur. Our research group has developed a test that can assess whether the heart muscle is struggling for blood. However, this test requires an invasive procedure and has only been tested in the sickest patients.

During this fellowship, Dr Sukhjinder Nijjer, will study a new non-invasive way of measuring how well the heart can maintain its blood supply in aortic stenosis. Dr Nijjer, a heart specialist in training, will use a combination of invasive and imaging tests in patients with different levels of aortic stenosis to measure the ‘reserve‘ blood supply available to the heart when extra work needs to be done. We aim to test the hypothesis that this reserve falls with worsening aortic stenosis. This work may provide a new non-invasive way of measuring the reserve to monitor the effect that aortic stenosis has on heart function, and aid the timing of aortic valve replacement before symptoms occur.

Technical Summary

Background: Exertional symptoms in aortic stenosis indicate necessity for valve replacement, but are mimicked by other conditions or masked by inactivity. Late intervention risks irreversible deterioration of cardiac function, whilst early intervention poses surgical risk without benefit. Increased afterload and ventricular remodelling alters microcirculatory physiology to cause myocardial ischaemia and symptoms. Determining the microcirculatory impact may guide intervention before irreversible damage occurs. This can be quantified using invasive wave intensity analysis utilising commercially available wires with pressure and Doppler flow sensors. We showed that in patients with severe symptomatic aortic stenosis, the intensity of microcirculatory-originating suction wave that drives coronary perfusion in early diastole, diminishes when the heart rate increases. This index, the coronary physiological reserve, corrects to a normal pattern of increased wave intensity, immediately after percutaneous aortic valve replacement. However, the impact of less severe aortic stenosis on the microcirculatory-originating waves and the coronary physiological reserve is undetermined. Furthermore, the invasive nature of the current technique limits its utility.

We have shown that it is feasible to measure coronary physiological reserve non-invasively using a Pulsecor assessment of central pressure and transthoracic coronary Doppler using a Philips iE33 echocardiography machine. During this fellowship, I will develop this technique and validate against its invasive equivalent. I will use both to assess the coronary physiological reserve in differing severities of aortic stenosis to understand the impact of increasing afterload.

Hypothesis:
1. Non-invasive coronary wave intensity and coronary physiological reserve are equivalent to their invasive counterparts.
2. Coronary physiological reserve is increased in mild-moderate aortic stenosis, but is decreased in subjects with moderate-severe aortic stenosis.
3. Myocardial blood flow as assessed by quantitative perfusion cardiac MRI is reduced in those with reduced coronary physiological reserve.

Study design: I will study coronary physiological reserve using both invasive and non-invasive techniques in 31 patients with aortic stenosis. I will also determine its relationship with myocardial blood flow measured by cardiac MRI.

Results: We anticipate that a dome-shaped parabolic relationship exists between increasing aortic stenosis severity and the microcirculatory wave intensity. The ‘tipping point‘ represents the onset of impaired myocardial perfusion; this may indicate necessity for intervention before the onset of symptoms.

Opportunity: This study will improve our understanding of coronary physiology in aortic stenosis. By using commonly available equipment it will provide a new objective, non-invasive measurement of the physiological significance of aortic stenosis to guide decisions for valvular intervention.

Publications

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Nijjer SS (2015) Advances in coronary physiology. in Circulation journal : official journal of the Japanese Circulation Society

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Nijjer SS (2014) Management of supraventricular tachycardias. in British journal of hospital medicine (London, England : 2005)

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Nijjer SS (2014) Diagnosis of supraventricular tachycardias. in British journal of hospital medicine (London, England : 2005)

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Nijjer SS (2011) The fluttering patient: an approach to the patient with palpitations. in British journal of hospital medicine (London, England : 2005)

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Nijjer SS (2012) Atrial fibrillation. in British journal of hospital medicine (London, England : 2005)

 
Description AFFECTS 
Organisation San Carlos University Hospital
Department Cardiovascular Institute
Country Spain 
Sector Academic/University 
PI Contribution The AFFECTS study was conceived, designed and performed by our team. We did the data analysis and provided over 50% of the data.
Collaborator Contribution The team at San Carlos and St Thomas' have contributed raw physiological data for the AFFECTS study - the largest invasive assessment of vasodilator impact on aortic reservoir pressure
Impact Has lead to a publication in press: JACC Cardiovascular Interventions
Start Year 2012
 
Description AFFECTS 
Organisation St Thomas' Hospital
Department Rayne Institute, St Thomas' Hospital
Country United Kingdom 
Sector Academic/University 
PI Contribution The AFFECTS study was conceived, designed and performed by our team. We did the data analysis and provided over 50% of the data.
Collaborator Contribution The team at San Carlos and St Thomas' have contributed raw physiological data for the AFFECTS study - the largest invasive assessment of vasodilator impact on aortic reservoir pressure
Impact Has lead to a publication in press: JACC Cardiovascular Interventions
Start Year 2012
 
Description DEFINE-FLOW 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution We are contributing patient recruitment and invasive physiological data to the multi-centre international study
Collaborator Contribution The AMC is responsible for the design and administration of this study
Impact Pending
Start Year 2013
 
Description IDEAL 
Organisation San Carlos University Hospital
Country Spain 
Sector Hospitals 
PI Contribution World's largest intracoronary pressure and flow velocity database (567 vessels). I have collated, analysed and processed the database; I contributed with personal data collection at least 25% of the total data. I have written the publication resulting from this collaboration.
Collaborator Contribution Imperial, VUMc, AMC and Clinico San Carlos all contributed intracoronary pressure and flow velocity measurements from patients undergoing invasive assessment.
Impact Manuscript has been prepared; due for submission.
Start Year 2014
 
Description IDEAL 
Organisation VU University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution World's largest intracoronary pressure and flow velocity database (567 vessels). I have collated, analysed and processed the database; I contributed with personal data collection at least 25% of the total data. I have written the publication resulting from this collaboration.
Collaborator Contribution Imperial, VUMc, AMC and Clinico San Carlos all contributed intracoronary pressure and flow velocity measurements from patients undergoing invasive assessment.
Impact Manuscript has been prepared; due for submission.
Start Year 2014
 
Description IDEAL 
Organisation VU University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution World's largest intracoronary pressure and flow velocity database (567 vessels). I have collated, analysed and processed the database; I contributed with personal data collection at least 25% of the total data. I have written the publication resulting from this collaboration.
Collaborator Contribution Imperial, VUMc, AMC and Clinico San Carlos all contributed intracoronary pressure and flow velocity measurements from patients undergoing invasive assessment.
Impact Manuscript has been prepared; due for submission.
Start Year 2014
 
Description JUSTIFY 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Collaboration of invasive physiological data
Collaborator Contribution Equal contribution of data and sharing of manuscript writing and analysis; We have provided the data analysis software and techniques
Impact Three publications are in press
Start Year 2013
 
Title iFR Pullback 
Description iFR has been developed by Justin Davies as part of our overall group activity; he furthermore developed the iFR-Pullback algorithms which I have tested in man and lead to their refinement. The approach is a simpler technique than what is currently used in patients. The tool is currently in process of being developed into a commercially available clinical diagnostic tool for use in patients with multiple coronary stenosis - to help clinicians decide which require stenting first. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact This tool is still being investigated but has been licensed Volcano Corporation to be developed into a commercial tool 
 
Description Big Bang London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Massive event with several thousand attendees to observe live work-shops of cardiac investigation and treatment

Excellent feedback from organisers
Year(s) Of Engagement Activity 2013
URL http://www.thebigbangfair.co.uk/london/Home/
 
Description ESC Working Group: Coronary Pathophysiology and Microcirculation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited to be part of ESC Working Group on Coronary Pathophysiology and Microcirculation; facilitator role

Consolidated links with Dr Javier Escaned with subsequent data exchange
Year(s) Of Engagement Activity 2013
URL http://www.escardio.org/communities/Working-Groups/coronary-microcirculation/Pages/welcome.aspx
 
Description EuroPCR 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Oral Presentation of key findings of research

Discussion with an interested research group that lead to a collaboration
Year(s) Of Engagement Activity 2013
URL http://www.europcr.com
 
Description PACE 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Over a 100 Cardiologists interested in Coronary Physiology attended a weekend course to discuss and advance understanding

Discussions with industry regarding development of pullback data that I have collected
Year(s) Of Engagement Activity 2013
 
Description TCT 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Lead to collaboration with Dutch team from Amsterdam Medical Center

Lead to collaboration with two new international studies
Year(s) Of Engagement Activity 2012
URL http://www.tctconference.com/
 
Description TCT 2013 Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact TCT 2013, San Francisco USA

Presented:

TCT-620 Mean Hyperemic Flow is Not Increased Following Adenosine Administration in Physiologically Significant Lesions


Sparked interest in future publication
Year(s) Of Engagement Activity 2013
URL http://www.tctconference.com/