Posts Tagged ‘Imperial College London’

Implications of Inheritance for Clinical Management: Common Cardiovascular Disorders When There Is a Family History

Reporter: Aviva Lev- Ari, PhD, RN


A Clinical Approach to Common Cardiovascular Disorders When There Is a Family History:  The Implications of Inheritance for Clinical Management

Srijita Sen-Chowdhry, MBBS, MD, FESC, Daniel Jacoby, MD and William J. McKenna, MD, DSc, FESC

Author Affiliations

From the Institute of Cardiovascular Science, University College London, London, United Kingdom (S.S-C., W.J.M.); Department of Epidemiology, Imperial College, London, London, United Kingdom (S.S-C.); Division of Cardiology, Yale School of Medicine, New Haven, CT (D.J., W.J.M.).

Correspondence to Professor William J. McKenna, MD, DSc, FESC, Institute of Cardiovascular Science, University College London, The Heart Hospital, 16-18 Westmoreland Street, London, E-mail william.mckenna@uclh.nhs.uk


Since the advent of genotyping, recognition of heritable disease has been perceived as an opportunity for genetic diagnosis or new gene identification studies to advance understanding of pathogenesis. Until recently, however, clinical application of DNA-based testing was confined largely to Mendelian disorders. Even within this remit, predictive testing of relatives is cost-effective only in diseases in which the majority of families harbor mutations in known causal genes, such as adult polycystic kidney disease and hypertrophic cardiomyopathy, but not dilated cardiomyopathy. Confirmatory genetic testing of index cases with borderline clinical features may be economic in the still smaller subset of diseases with limited locus heterogeneity, such as Marfan syndrome. Furthermore, Mendelian diseases account for ≈5% of total disease burden.1 Genome-wide association studies have made headway in elucidating the genetic contribution to the more common, complex diseases, and high throughput techniques promise to facilitate integration of genetic analysis into clinical practice. Nevertheless, many genes remain to be identified and implementation of genomic profiling as a population screening tool would not be cost-effective at present. The implications of heredity, however, extend beyond serving as a platform for genetic analysis, influencing diagnosis, prognostication, and treatment of both index cases and relatives, and enabling rational targeting of genotyping resources. This review covers acquisition of a family history, evaluation of heritability and inheritance patterns, and the impact of inheritance on subsequent components of the clinical pathway.


Circulation: Cardiovascular Genetics.2012; 5: 467-476

doi: 10.1161/ CIRCGENETICS.110.959361


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Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels

Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The evaluation of coronary artery disease (blocked arterial blood supply to heart muscle) by stress tests is functional: is there enough blockage to starve a region of muscle when demand is high? By starvation we mean ischemia – insufficient supply to meet metabolic demands as expressed by consequent functional impairment, e.g., metabolic, electric, mechanical. In the catheterization laboratory, the evaluation is primarily anatomic – is there a bite missing in the silhouette of a coronary artery consistent with a significant impediment to blood delivery beyond the lesion? Half of all heart attacks are due to such lesions. The other half derive from non-obstructive but unstable lesions that may crack, bleed into the vessel wall, and suddenly clot,  blocking the blood flow. Coronary lesions that restrict blood delivery sufficient to cause demand ischemia (insufficient blood supply to meet high demands) cause angina pectoris.

The focus of flow reserve is to add an assessment of functional significance to anatomic lesions observed at catheterization. The widespread practice of deciding on intervention based on percent diameter reduction imposed by a lesion is obviously flawed. The flow limitation imposed by a lesion depends on its length and shape (entrance and exit effects on flow pattern), not merely the diameter reduction expressed as a percent, that is currently deemed the decision-making “degree of stenosis.” In the midst of a medical emergency heart attack, the target of intervention is the culprit lesion, the one that best explains why a region of muscle is dying. In that case, timely intervention is potentially life saving and does not depend on or wait for measurements. In the non-emergent setting, it is much harder to establish benefit from intervention. If a lesion is flow limiting and explanatory for angina pectoris, then intervention to relieve obstruction offers pain relief and may improve exertion tolerance. In relatively rare circumstances (3-vessel obstruction, left main obstruction) intervention may avoid heart attack and extend life expectancy, but with as good or better outcomes from bypass surgery. Most elective catheter interventions (balloon angioplasty, stent placement) have failed  to establish improved life expectancy or even superiority over medication. Furthermore, stent placement obligates use of strong anti-platelet medications (e.g., aspirin plus clopidogrel) that elevate risk of serious bleeding and stroke. Therefore it is reasonable to require further evidence that a coronary lesion is obstructive and consequential that just percent stenosis (narrowing) as indication for intervention. Fractional flow reserve offers such confirmation of lesion significance.

Fractional flow reserve may prove useful also in the definition of heart attack (myocardial infarction): New Definition of MI Unveiled, Fractional Flow Reserve (FFR) CT for Tagging Ischemia

June 21, 2013

Recorded: May 23, 2013



The use of FFR is relatively widespread in Europe, while its usage is beginning to catch up in the US. But for what reasons? Drs Roxana Mehran,Justin Davies, and Ron Waksman gathered recently to share their thoughts on the role of functional assessment in the cath lab, to evaluate FFR and its alternatives, and discuss what testing the future might hold for the optimal detection of culprit lesions.


Roxana Mehran MD
Professor of Medicine, Divisions of Cardiology and Health Evidence and Policy
Director, Interventional Cardiovascular Research and Clinical Trials
The Zena and Michael A Wiener Cardiovascular Institute
Icahn School of Medicine at Mount Sinai
New York, NY

Dr Mehran has served as an advisor or consultant for AstraZeneca Pharmaceuticals, Regado Biosciences, Abbott Cardiovascular Systems, Janssen (Johnson & Johnson), Merck, and Maya Medical. She has received grants for clinical research from Bristol-Myers Squibb, Sanofi, the Medicines Company, and Lilly/DSI.


Justin Davies MBBS PhD
Consultant Interventional Cardiologist
Hammersmith Hospital
Imperial College
London, United Kingdom

Dr Davies has served as an advisor or consultant for Volcano and Medtronic. He has served as a speaker or a member of a speakers’ bureau for Medtronic and has received grants for clinical research from Volcano, Medtronic, and Abbott.

Ron Waksman MD
Director, Clinical Research and Advanced Education
MedStar Cardiovascular Research Network/Cleveland Clinic Heart and Vascular Institute
Clinical Professor of Medicine (Cardiology)
Georgetown University
Washington, DC

Dr Waksman has served as a speaker or a member of a speakers’ bureau for AstraZeneca Pharmaceuticals, Boston Scientific, and Medtronic.

Roxana Mehran, MD: Hello. My name is Roxana Mehran from Mount Sinai

School of Medicine in New York. It’s my pleasure to welcome you to this editorial

program in which we will look into how FFR usage differs in Europe vs the United


I’m joined by my colleagues Justin Davies from Imperial College London and, of

course, Ron Waksman, an old friend, from the Washington Hospital Center in

DC. Welcome.

Ron Waksman, MD: Thank you.

Dr Mehran: We thought today we’d have a conversation about fractional flow

reserve and the use of functional studies in guiding our interventional

procedures. This has become a very interesting and important modality that has

been incorporated, now, more and more into the cath lab.

Let’s begin, Justin. Maybe you could tell us: what is FFR? How do we use it?

What do you think about it? How important is it to have? Does every cath lab

need to have FFR?

Justin E Davies, MD: I think that it provides cath labs with an objective measure

of stenosis assessment that is quick and relatively easy to use. Often you find

people don’t come to cath labs with preprocedural ischemic assessment, so it

enables a physician in the lab to see if there is ischemia and to effectively

document that. It has clearly got a good, strong evidence base, which has been

developed over a number of years with the founding studies of DEFER and

FAME—and FAME-2, now, which has led to the technique getting into guidelines

and which has propelled its use to widespread practice.

Dr Mehran: There’s no question that functional assessment is quite important,

but what do you think about patients coming into the cath lab, especially in the

United States, without an ischemic assessment? How often are you seeing that

and would you even use [FFR] in a patient who has got a 90% stenosis or 80%

stenosis, Ron?

Dr Waksman: I think we are in a period of transformational culture, now, in terms

of appropriate-use criteria and justifying every lesion that we are doing. I think

that interventional cardiologists are on the defensive—because we have to justify

almost any angioplasty that we are doing, especially with an intermediate lesion.

I think physicians are more flexible in using FFR and looking it as guidance to

support their decision-making.

I would say, still, if it is a 90% lesion even without a functional test I don’t think it

is required, but the 90% is on the eyes of the beholder, so you know that if you

take it to the core lab it is not going to be probably 90%, it is usually going to be

less than that.

And as you know, we have been scrutinized by looking at films and, again, [we

need to] justify. It is true that in the past the algorithm was having a functional

test and going to the cath lab. But this [step] has delayed things, and now people

presenting with some chest discomfort, [who] have risk factors, they sometimes

would be sent to the cath lab as the first method of assessment. I think we have

to take this more carefully and incorporate a functional ischemic assessment in

the cath lab—especially when those lesions are not necessarily unambiguous,

we don’t clearly know that they would derive ischemia.

Dr Mehran: It seems like that is really the way to go. You talked to us about

FAME, FAME-2, [that FFR is] the only modality in the cath lab that actually

improves hard end points like death and MI. I think that was how it got into the

guidelines, obviously. Very important studies. But at what cost? Can we afford to

do this in every single patient who presents with, let’s say, multivessel disease,

as they did in FAME?

Dr Davies: I think, actually, that this is a tremendous opportunity because I think

for us as cardiologists, as Ron said, it is very easy to get yourself into a little bit of

a hole stenting lesions that are not as significant as you may think, and I think

this obviously provides a justification and a safety net for people to deploy stents.

But also I think increasingly going forward when you are taking on potentially

more challenging techniques and you have got three-vessel disease, [FFR]

enables us to assess multivessel disease and perhaps convert a three-vessel

PCI into a two- or [even] a single-vessel PCI, which may move them from getting

a CABG to angioplasty.

Dr Mehran: So actually decreasing the number of stents. Reducing your

devices—hopefully even radiation exposure and contrast media. If you actually

just do an FFR and say, okay, I am done. But you know that we have all

[discussed]: if you want to treat the lesion you use an IVUS; if you don’t want to

treat the lesion you use an FFR. What do you think about that, Ron? Is that

something that is going on in your lab?

Dr Waksman: No. We try to stay away [from that]. I know that is said. But I

would still think that FFR is oversold. For the controversy, I would [argue] that

those studies were investigator-sponsored studies and I don’t think the data are

so relevant today. In DEFER there was a balloon angioplasty. Even in FAME-1, it

was with first-generation stents, and it was not really practice to go after every


I think we have to take these [data] with a grain of salt. To my view, not

everything is definitive. Nevertheless, we do see uptake of the FFR usage in the

lab and for something that used to be under 3% in the US—only a couple of

years ago—it is now reaching up to 20%. More and more people are using [FFR].

There are other modalities that you can use. I think that we try to do a conversion

between the anatomical [minimum lumen area] (MLA) to the IVUS / FFR. It is

controversial, but it is another option. I think we need to learn to use the tool

when we really need it, not to be obsessed with it.

Often, we would have a scenario [where] a patient presents with chest pain. It is

classical angina. It is relieved by nitroglycerin. You have what you think is about

70% lesion in the proximal LAD and then you stick [in] the FFR wire and you get

0.81. Then you have a problem. You can repeat the study. You shoot another

adenosine and now it is 0.79. Then you shoot another one and it is 0.80. It is very

hard for me when you have a binary number to make a decision [based] on that

number. I don’t think we should lose our clinical judgment. It is a nice tool, but

don’t abuse it. Use it when it is really helpful.

Dr Davies: I will share my view. I have to say I agree wholeheartedly with Ron.

To me, if you ask them what are the most important numbers in FFR, people will

say: 0.80 or 0.75. Actually, I think the two most important numbers are 0 when it

is completely occluded and 1. As you get nearer to 0.80 you know that you are

approaching a place where it is going to be likely ischemia and a high probability

of events. Ron is absolutely right. If you have a type A, 90% lesion and you have

an FFR of 0.81—I know [that] in the US you are in difficulties, at the moment,

with these kinds of lesions. I think with the commonsense kind of medical

entirety/holistic approach that would say you should probably stent these people.

Dr Mehran: But isn’t that just so important? Those are really important points

because it is not about the dichotomous number of 0.80 or 0.75. It is about the

clinician and what they feel the scenario is and how it all fits together.

Dr Waksman: I would say even though it is getting very hard to support by

studies but I may not have an 80% or 70% lesion. I would rather have an FFR of

0.92 or 0.96 than 0.81.

Dr Davies: Absolutely.

Dr Mehran: Of course.

Dr Waksman: If I have the choice. You also have to realize that the stents of

today are not the stents of yesterday. I think we see [many fewer] events. I think

that the price of stenting and the likelihood that we would have events is much

lower than in the past. So even if we deviate a little bit, it I don’t think we do an

injustice to the patients [or] put them at high risk. I would challenge that if you

would [do] the same study today as DEFER, with the new second-generation

stents, I am not sure that the results would be the same—as robust—as they

were in the past. As a matter of fact, if you are looking even [at] FAME-2, at the

two groups—[those who] were medically treated and those who were

[interventionally] treated, the curves were actually very similar. I would challenge

that you [would not be replicating these results] with second-generation [stents].

You have to be taking [FFR] when you really need. I don’t think [that]

systematically you go [to] every lesion and if it meets the criteria of 0.80, you

don’t treat. If it is less, you treat.

Dr Davies: And there are some people who see this as a weakness, but we

don’t do that in any other form of medicine we practice, and I see it as a strength

that you get a continuous range of values. I think the one thing, which we have

also done, is using these techniques purely as an outcome base. But really if you

look back they were designed to describe ischemia and chest pain, so really it is

a very good tool for seeing if chest pain is genuine and if it is likely to benefit from

a stent.

Dr Mehran: That’s right.

Dr. Davies: And that hasn’t been thoroughly explored since the original studies.

Dr Mehran: Those are really excellent points. Now, we have alternatives to FFR.

We talked a little bit about IVUS, but we also know now that, Justin, you have

done a lot of the work on [instantaneous wave-free ratio] iFR. Maybe you can just

tell us: what is iFR? How is it different from FFR and where are we in that? Do

you believe it will replace FFR?

Dr Davies: iFR is a technique which is very similar to perform as FFR. You use

the same pressure wire. It is a software change in the console that essentially

allows us to make a measurement of stenosis severity over a particular phase of

the cardiac cycle without the need for a drug. It typically takes a few seconds to

measure and is very quick.

There have been, to date, about 3000 patients studied, in five clinical trials,

which—with the exception of one study—have all shown, essentially, the same


And we know at the EuroPCR meeting this was, again, replicated this week. At

the moment, we are in a situation where we are advocating the use of a hybrid

approach, similar to the big RESOLVE study, which essentially says that if you

are above an iFR threshold of 0.93 you are safe to defer and below 0.86, to treat.

That gives you about a 90% to 95% agreement with FFR and overall

classification, and the ADVISE-II study shows it saves about 70% of adenosine.

There are potentially quite marked savings in the cath lab.

I think this is out there in clinical practice—in a limited release, in terms of certain

labs around the world on three continents. The general experience has been

very, very good from people in terms of just facilitating the use of physiology.

What I mean by that: I take centers that were relatively small users of FFR and

they found they have done the same number of cases in three months as they

would have done over the whole year. If you ask them why, it’s because it lowers

the burden of doing [the cases]. I think if we then move on to doing triple-vesseldisease

assessment I think it takes five seconds of each.

Dr Mehran: I think there is no question that taking away the adenosine is music

to a lot of people’s ears. We all know that adenosine is not being given perfectly

right in certain laboratories. It really should be an intravenous injection. There is

time needed for nurses to put it together, to put in the IV, the intra-arterial

[injection] has been refuted, etc.

But when I look at iFR I start to think that we are pushing ourselves toward what

Ron was just talking about. I think the validations need to take place. It would be

great to have technology that is well validated, studied, that actually correlates

with events without adenosine. I think that part of it is brilliant. But are we there


Dr Davies: We have had a very good response taking the stuff from the research

lab into the cath lab, so this is what we are using this as a tool, certainly, within

the framework of studies. I think now we are in a position to do large studies. I

will give you an example: we asked all of the investigators who have got these

machines if they are willing to contribute to analysis at the time of PCI. [In the

space of] for four weeks—most of them only had the device that length of time,

they managed to get together 400 cases. [This shows that] doing very large

studies of 1500 or 2000 patients is extremely feasible and very easy to do.

Dr Mehran: I hope you are designing them and actually performing them.

Ron, what do you think about iFR? I love to hear your scrutiny.

Dr Waksman: I think it hasn’t been validated, obviously. I [would] like to get rid of

the adenosine. But I like to see reproducibility of any test. Again, I would say, we

don’t have to lose our brains just because we have numbers. We have a patient

in front of us. He has symptoms and we have lesions that we have to treat.

Obviously if you have a proximal lesion, it’s going to behave differently than a mid

or distal vessel. We know that, for example, if you look at most of the studies, at

just a circumflex of FFR. Most of them will be above 8.0. But you take most

proximal LADs, they probably would fit more into the predictability of ischemia vs

nonischemia. We have to, again, use our brains when we use the numbers and

understand what they mean.

I think that there will be other technologies that [will] try to be alternatives to

FFR—not that FFR is necessarily bad, but there are other ways that you can do

it. There is the heart flow option with a CT. I still think that IVUS is an option.

Not all of them are ideal, but it gives you a variety of options. The message is: we

are trying to treat only the vessels that need to be treated. I think that can also

change the paradigm of treatment. For example, we may turn “three vessel” to

“one vessel” and change the whole syntax score and move patients from CABG

to PCI—which is very attractive for interventional cardiologists.

One other thing that is interesting: recently I heard that SJ Park was presenting a

systematic use on all patients with FFR—which is amazing! It is over 70%. It was

not a randomized study but what he did show by systematically using FFR in his

practice [is that] he reduced, by a lot, the number of PCIs, the number of stents,

and the outcome of those patients was good. You have to compare it in a

randomized fashion. What would be the alternative? And that is the challenge.

You really have to show [efficacy] in a randomized clinical trial. I recognize there

were studies in the past, but they have limitations. I think we [are] moving to

another phase that this has to be tested.

Dr Mehran: Quickly touching on what you just said about noninvasive functional

assessments. More and more we are getting patients who come in with a

multislice CT. Can we use that technology to actually do some of the functional

assessment right then and there? The DEFACTO trial, in my mind, is a negative

study. Where are we with that technology?

Dr Davies: You are absolutely right to say a lot of these patients have CTs and it

is a question of whether we can use information from that CT. As Ron said, there

is HeartFlow technology, which enables you to effectively get a noninvasive

preprocedural virtual FFR measurement. Certainly from a theoretical perspective,

it should be possible to do these calculations. I think the problem that the

HeartFlow team has is translating the computational flow dynamic theory in a

perfect research environment into the clinical practice of getting good-quality

CTs. I think there is probably more work in progress to see that really translate.

Dr Mehran: That’s right.

Dr Waksman: But what we are seeing in the US right now is [that] there is a

decline in the nuclear test and there is increased uptake in FFR. There is a

change in paradigm because of many reasons. Some of them have nothing to do

with medicine. It is more the reimbursement. Because reimbursement went down

on nuclear tests, we see less nuclear tests being performed. Now we are getting

the patients actually to be assessed in the lab and we get [to have] more

confidence with FFR or other technologies. I think we are shifting the traditional

assessment of ischemia, which was in the old days was nuclear or dobutamine

echo, more into those [tests performed] in the lab. And I do believe that the fact

that studies were negative is not the end of the story. We still have to fine-tune.

This is all about software validation and finding the sweet spot. What is the

window that allows you to get good matching? That you can feel comfortable


Dr Mehran: So great technology to look forward to in the future. We are looking

for that kind of noninvasive assessment of functional studies. Let’s now turn to

why we are really here, which is about the regional differences of FFR. In the UK,

in Europe, in the United States, are there regional differences? Let’s better

understand that. And, if so, why? Justin, maybe you could tell us about the UK

and Europe?

Dr Davies: I think [FFR penetration] is somewhere between 15% and 20% of

cases in the UK, which is very high on a worldwide basis. I think some of that has

to do with reimbursement and some of it is to do with the way that doctors are

reimbursed, as well. In terms of the UK, if we put a stent in or not, it has no net

effect on the income to ourselves. So it is very easy for us to follow guidelines

and, in fact, if we don’t, [we] get rapped around the knuckles and told off for not

doing so. I think that is a strong incentive to do it.

I think there are obviously differences from us in other parts of the world with

regard to the reimbursement—the cost of the bits of kit and the availability of the

kit. In some labs around the world, and some territories, getting adenosine is

simply not possible or it is [so] outrageously expensive that people would just say

I am not going to make this measurement and they defer to angiography or, as

Ron said, to IVUS.

Dr Mehran: It seems like the penetration is a little bit the same between the UK

and US? What do you think about the United States?

Dr Waksman: Not yet. I would actually take from what Justin just said. I think

that the main motivation in Europe for the penetration of FFR was monetary. It

was actually to save money to the operator, to the cath lab. This never was the

case in the US. I think the in the US of the uptick is more related to

the appropriateness[-criteria guidelines] and to be on the defensive. The

interventionalist now has to defend himself for every procedure [he is] doing and

to have a backup [as to] why they did this procedure. That was not the case in

the European continent, [where] the main drive was to reduce overall costs on

the capitation system. I always had a problem with that because this is the way

that it was presented and I think that we should give the best to our patients.

We also have to realize that the reason for the uptick could be because of

appropriateness. We actually learned to turn this into a helpful tool for us [and] to

use it not just for those ancillary decisions—that probably should not be related to

the patient (whether it is a cost or whether it is appropriateness), but [also for]

what [it is] really good [for]: to see how we can utilize [it] to do the right procedure

to the right vessel. So it’s another tool.

But as I mentioned before, I think we are seeing an uptick. I don’t think we are

crossing the 20% and we are not as broad as in Europe. When are we going to

get there? It is a question of how much push we are going to see, but one thing

you see [now is] more companies providing FFR systems. That means that there

will be more reps in the labs and more opportunities, and that is usually what will

populate the usage of the device. I have no doubt that we are going to continue

to see an increase.

Dr Davies: It is interesting. I know from the US, and some of the data there,

there is a big difference between diagnostic use of FFR and actually the PCI use.

It is almost used in the US to justify PCI, and I think the angiography use is

somewhere around 3%. If you take that study that SJ Park has just done and you

compare that 70% percent that he was doing with the 3%, there is obviously a

huge potential.

Dr Mehran: Isn’t it interesting that maybe the driving force of doing a functional

assessment in the lab is different in the UK vs the US or Europe vs the United

States? I believe that at the end of the day they both will come to the same

conclusion of doing the right procedure to the right patient, making the correct

diagnosis, treating the right lesion for the right patient, but at the end of the day

actually decreasing costs. While maybe we are seeing in the United States that

appropriate-use criteria is why we are doing this, it has, perhaps, to do with

capitation, as well, for us in the United States, and enhancing the cost in the

system, hopefully, with this kind of functional assessment?

Dr Waksman: I think there is one more important collateral benefit from using

the FFR. That I would say is that we are changing the paradigm. In the old days

we thought we have to treat all the three vessels; we have to have complete

revascularization. I think FFR taught us that actually we may not need to treat all

the three vessels. That is a big advantage of technology. As we are using it we

are starting to see maybe we just have to treat the culprit lesion and move on

and then leave the others either on medical therapy or not treat them at all. That

is a huge change in paradigm.

Dr Mehran: This has been a fantastic conversation among the three of us, and I

just want to close and I want you each to close for me. What do you think is the

future of FFR? What should we be looking forward to as alternatives and what

incorporation of functional assessment in the cath lab as we move to the next

decade of interventional cardiology. Ron?

Dr Waksman: I think that the FFR will continue to grow. I think that there is a

good future for iFR without the adenosine, the wireless, and better wires that you

can use. I think you [could] incorporate an IVUS probe in them—FFR on an IVUS

probe, so you can do both. I think that the combination of anatomical and

physiological [testing] is important. We learned that with IVUS you can optimize

the outcome of the PCI, not only just determine whether you treat or not. So the

future is there. We are coming to do more sophisticated PCIs, and these data will

help us to get better outcomes and also to triage the patients to what should be

the treatment of choice. In the long run—even though the short run shows

reduction of the PCIs—if we use [FFR] carefully it will open us or enable us to do

more complex patients and meet the outcome that is expected.

Dr Mehran: That’s great. Justin?

Dr Davies: I would agree with Ron’s thoughts and also extend them to say I think

we will be doing more of these measurements, but I also think we should be

doing more smartly. As we discussed earlier, if you get these very borderline

lesions in patients who clearly have angina, then this is an indication for treating

your patient and looking at the patient as a whole.

I think we are really going to embrace technology. Medicine is always a little bit

behind the kind of technological leaps compared with smartphones, for instance.

I think techniques such as the HeartFlow technique, techniques such as the ones

we have been working on with iFR, I think will continue to move forward. I think

whereas we only today have discussed things from the purely diagnostic single

ischemic perspective, I think within one or two years you are going to have

techniques freely available in the cath lab that enable us to coregister the

FFR/iFR images onto angiogram in real time, enable you to plan PCI by selecting

which lesions may or may not benefit from therapy, even before you deploy a

stent. I think this, in the SYNTAX era, where we know the potential benefits of

minimizing angioplasty, like Ron said, will really facilitate our practice, and I

suppose the most important thing is lead to the better results for our patients.

Dr Mehran: I think that you both did a beautiful job telling us about the current

and the future technology and even if there are regional differences, at the end of

the day what we are trying to do is use the functional assessment to enhance

outcomes for our patients with cardiovascular disease, to make the right

diagnostic and therapeutic choices in these patients. And the combination of

these technologies that currently exists and hopefully will exist in the future will

absolutely get us there.

Thank you so much for your time this morning and I hope our audience enjoys

this conversation as I did. Thank you.




On this Open Access Online Scientific Journal the following articles published cases and results on Tools for Ischemic Assessment

 Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation


Detection and quantification of myocardial perfusion … – MDLinx


CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC


Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA


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Reporter: Aviva Lev-Ari, PhD, RN

J Cardiovasc Transl Res. 2012 Sep 7. [Epub ahead of print]

Next Generation Diagnostics in Inherited Arrhythmia Syndromes : A Comparison of Two Approaches.

Ware JSJohn SRoberts AMBuchan RGong SPeters NSRobinson DOLucassen ABehr ERCook SA.


MRC Clinical Sciences Centre, Imperial College London, London, UK, j.ware@imperial.ac.uk.


Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and “hot spots” in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.

PMID: 22956155 [PubMed]

Researchers in the UK have compared a PCR-based and a capture hybridization-based assay for sequencing panels of inherited cardiovascular disease genes and have found both to be suitable for diagnostics in principle, though their sensitivity needs to be optimized.

According to James Ware, a clinical lecturer at Imperial College London, the purpose of the study, published online this month in the Journal of Cardiovascular Translational Research, was to evaluate different approaches for sequencing cardiovascular disease genes, both for molecular diagnosis and for large-scale resequencing research studies.

His group, in the National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit, is interested in a range of inherited heart disease types, including cardiomyopathies and inherited arrhythmia syndromes such as long QT syndrome.

For their study, they compared two next-gen sequencing assays: a PCR-based approach that uses Fluidigm’s Access Array to amplify 96 amplicons in five LQT genes and one other gene, followed by sequencing on the 454 GS Junior; and an in-solution hybridization approach that uses Agilent’s SureSelect to target 49 inherited arrhythmia genes and sequences them on Life Technologies’ SOLiD 4.

The study focused on the sensitivity of the assays, or how well they were able to capture their intended targets, rather than their specificity, or their ability to avoid false positives.

Ware said that at the time of the study, PCR and in-solution capture were the two main target selection methods available. The researchers are still using both approaches but are now employing “a wide range of sequencers” from various providers for both types of assays, including Illumina instruments and Life Tech’s Ion Torrent.

For their comparison, they analyzed 48 samples, of which they sequenced 33 with both approaches and 15 using either one or the other.

The samples included 19 known variants in three disease genes, of which the hybridization-SOLiD method detected 17 and the PCR-454 method 14. Undetected variants were generally in areas that were not well covered, either due to a failure in enrichment, sequencing, or because the alignment was not unique. One variant that was missed by both approaches fell in a very GC-rich region.

Consumables costs for both assays were considerably lower than with Sanger sequencing: While sequencing five genes by Sanger costs more than $700 in consumables, the five-gene PCR/454 assay cost about $55 and the 49-gene hybridization/SOLiD assay cost about $200, according to the study.

Turnaround time is the shortest for Sanger sequencing, which, according to the study, can be done in one day for five genes and 17 samples, not including sample prep. The PCR/454 assay takes about two days for target enrichment and sequencing 48 samples, and the hybridization/SOLiD assay takes about two weeks for sequencing alone, they wrote.

Overall, Ware said, both sequencing approaches performed “reasonably well” and are significantly cheaper than Sanger sequencing. He said that in the UK, molecular diagnosis for inherited cardiovascular disease has traditionally been performed by Sanger, at a cost of approximately £500 to £1,000 ($800 to $1,600) for several genes involved in a clinical condition. However, for cost reasons, not all relevant genes are usually sequenced.

Target selection was the performance-limiting step for both approaches, a result the researchers expected. “It sounds obvious, but not all genes are equally easy to target,” Ware said. For example, in the hybridization assay, the overall target coverage was about 98 percent, but for some genes, it was only 80 percent or 90 percent. The two most important genes in long QT syndrome, KCNQ1 and KCNH2, “proved to be the hardest to sequence.”

Thus, for diagnostic use of NGS gene panels, “it’s important to know not just how the system performs overall but really how it’s performing for the specific genes you’re interested in,” he said.

To use either approach in diagnostics, the target selection step would need to be optimized. Ware’s team has already improved both assays and is now trying them in a number of fully Sanger-sequenced samples to study both sensitivity and specificity.

Longer term, the sensitivity of next-gen sequencing could approach that of Sanger sequencing, he said. And even if it does not reach 100 percent, because NGS approaches can target so many more genes, “maybe you can afford a very slight tradeoff in the per-gene sensitivity if the overall diagnostic sensitivity of the panel goes up,” he said. “At the moment, because we don’t have that much experience in sequencing the less-common genes, we don’t exactly know where that tradeoff lies.” In addition, any gaps could be filled by Sanger sequencing, while the test would probably still be cost effective.

Each approach also has some features that make it more suitable for certain applications. The PCR-based method has a fast turnaround and an “extremely user-friendly workflow,” Ware said, but it can only accommodate a small number of genes at the moment. His team also found it to be easier to optimize and improve. Thus, in the short term, PCR and sequencing “is probably closer to providing a diagnostic solution,” he said, especially for conditions where only a few genes are causative.

The hybridization-based approach, on the other hand, has much greater capacity, and there are advantages in “having a single assay that covers everything,” he said. It might also be possible to detect copy number variants using this approach, but not the more limited PCR method, he added.

Ware and his colleagues are currently using the hybridization approach to study a large panel of genes in 2,000 well-phenotyped volunteers, both healthy individuals and heart disease patients.

They have also started to use the hybridization method to sequence the TTN gene, truncating mutations in which were recently found to be a common cause of dilated cardiomyopathy. They are running the TTN test routinely for patients consented for research diagnostic testing that is not available anywhere else. Because this gene is so large, it is “completely impractical to be sequenced by conventional Sanger,” Ware said.

Julia Karow tracks trends in next-generation sequencing for research and clinical applications for GenomeWeb’s In Sequenceand Clinical Sequencing News. E-mail her here or follow her GenomeWeb Twitter accounts at @InSequence and@ClinSeqNews.


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