Posts Tagged ‘American Heart Association’

HOT TOPICS 2014: Heart – The medpage TODAY View

Reporter: Aviva Lev-Ari, PhD, RN

HOT TOPICS 2014: Heart – Medical 1
(Post Date: 1/2/14)



HOT TOPICS 2014: Heart – Medical 1
(Post Date: 1/2/14)
Steven Nissen, MD – Cleveland Clinic
Clyde Yancy, MD – Northwestern University, Feinberg School of Medicine
Robert Califf, MD – Duke Medical Center
Elliott Antman, MD – BWH


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American Association of Clinical Endocrinologists (AACE) can’t support the new cardiovascular risk guidelines issued by the American Heart Association (AHA) and the American College of Cardiology (ACC)

Reporter: Aviva Lev-Ari,PhD, RN

Endocrinology Group Rejects New AHA/ACC CVD Guidelines

Miriam E. Tucker

December 13, 2013

The American Association of Clinical Endocrinologists (AACE) says it can’t support the new cardiovascular risk guidelines issued by the American Heart Association (AHA) and the American College of Cardiology (ACC), saying the set of 4 guideline documents is out of step with its own recommendations.

“AACE was asked to review and endorse the obesity and cholesterol guidelines. After careful consideration by the appropriate scientific committees of our organization, AACE declined to endorse these new cholesterol and obesity guidelines,” the organization said in a statement that was sent to its members in November and forwarded to the media today. “There are multiple reasons for this decision, including, principally, the incompatibility of these new guidelines with our existing guidelines.”

The 4 guidelines are:

All of the guidelines were issued with the support of the National Heart, Lung and Blood Institute, which had last updated its Adult Treatment Panel 3 (ATP3) National Cholesterol Education Panel (NCEP) guidelines for cholesterol and lipid management in 2004. AACE had “generally agreed” with those guidelines.

AACE welcomes the intent of the AHA and ACC in the creation of these new guidelines but cannot endorse them.

The endocrinology group faults the new AHA/ACC guidelines for focusing exclusively on randomized clinical trials and for not including studies published since 2011. “They are highly restrictive regarding the database considered and omit much new information… Taken together, these actions have resulted in a considerable number of at-risk patients being omitted from consideration.”

And, AACE says that the new cardiovascular disease calculator that was published along with the guidelines—and generated the most controversy—is already outdated. “It is based upon outmoded data, does not model the totality of the US population, has not been validated, and therefore has only limited applicability.”

As for new lipid guidelines, AACE disagrees with removal of the LDL targets and the idea that statin therapy alone is sufficient for all at-risk patients, noting that many who have multiple risk factors, including diabetes and established heart disease, will need additional therapies.

Finally, the new obesity guidelines, AACE says, “fail to classify obesity as a disease and continue the paradigm of [body-mass-index] BMI-centric risk stratification, both of which are contrary to recently stated AACE positions.” In addition, newly FDA-approved weight-loss medications are not included.

The statement concludes, “AACE welcomes the intent of the AHA and ACC in the creation of these new guidelines but does not agree with the complete content and therefore cannot endorse them.”




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Resistance Hypertension: Renal Artery Intervention using Stenting

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 2/4/2014

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

Christopher J. Cooper, M.D., Timothy P. Murphy, M.D., Donald E. Cutlip, M.D., Kenneth Jamerson, M.D., William Henrich, M.D., Diane M. Reid, M.D., David J. Cohen, M.D., Alan H. Matsumoto, M.D., Michael Steffes, M.D., Michael R. Jaff, D.O., Martin R. Prince, M.D., Ph.D., Eldrin F. Lewis, M.D., Katherine R. Tuttle, M.D., Joseph I. Shapiro, M.D., M.P.H., John H. Rundback, M.D., Joseph M. Massaro, Ph.D., Ralph B. D’Agostino, Sr., Ph.D., and Lance D. Dworkin, M.D. for the CORAL Investigators

N Engl J Med 2014; 370:13-22 January 2, 2014DOI: 10.1056/NEJMoa1310753


Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain.


We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy).


Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P=0.03).


Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.)



based on

What Do CORAL and ERASE Mean for Peripheral Intervention?

Seth Bilazarian, MD, Mark A. Creager, MD

November 27, 2013

Seth Bilazarian, MD: Hi. I’m Seth Bilazarian from the heart.org on Medscape. I’m here at the American Heart Association Scientific Sessions in Dallas with Dr. Mark Creager, Director of Vascular Medicine at Brigham and Women’s Hospital in Boston. Dr. Creager was the moderator of a session enriched with peripheral vascular disease topics yesterday. And I’m fortunate to be with him to unpack 2 of those studies: the ERASE study,[1] a study of peripheral artery disease in the lower extremities and exercise; and the CORAL study,[2] a study of renal artery intervention using stenting.

As a practicing endovascular medicine physician, I’m excited to get Dr. Creager’s take on this. The CORAL study, to start with, was a study that was sponsored by the NHLBI (National Heart, Lung, and Blood Institute), -looking at patients who had greater than 60% stenosis who had resistant hypertension or renal insufficiency and were optimally treated with medical therapy. The patients were given free antihypertensive therapies and statin therapy. And that alone was compared with medical therapy plus renal artery intervention with stenting.

Dr. Creager, can you summarize the take-home message and the results for our audience?

Mark A. Creager, MD: Thank you, Seth. This was an important study. The CORAL study compared these 2 groups, and the primary endpoints were cardiovascular and renal death, hospitalization for congestive heart failure, stroke, myocardial infarction, progressive renal insufficiency, and renal replacement therapy. The trial found that there was no significant difference in this primary composite endpoint between the 2 groups.

That’s an important message: that if we treat our patients with hypertension and renal insufficiency who have concomitant renal artery stenosis with appropriate medical therapy, they will do as well — in terms of cardiovascular and renal endpoints — as those who undergo renal artery stenting.

Dr. Bilazarian: A very strong message that stenting adds nothing, if we take home the short answer that renal stenting adds nothing on top of optimal medical therapy. Previously, enthusiasts for renal stenting criticized studies such as ASTRAL[3] and STAR[4] that the patients may not have been optimally chosen and may not have had significant enough renal artery stenosis.

In the CORAL study, we saw yesterday that in a subgroup analysis looking at patients who had greater or less than 80% stenosis, the average was 72% in the whole trial. But those at greater than 80% did not seem to fare any better from this study. They were the same as those at less than 80%. So does this largely close the door to renal stenting for atherosclerotic disease?

Dr. Creager: As implied by your question, one might have anticipated that those individuals with the most severe renal artery stenosis would have been those most likely to benefit. But as you stated, there was no difference between the patients who had a greater than 80% stenosis and those who did not. That really continues to raise questions about the efficacy of renal artery stenting in this population in general.

But it doesn’t entirely close the door. I think it still is very important for all physicians to deal with their patients individually and inform their decisions by the evidence that’s available. But there will be patients who have hypertension and remain refractory despite aggressive and appropriate medical therapy. And in those individuals, one might consider looking for the presence of renal artery stenosis, and if found, treat them.

But keep in mind that in this trial, the group randomized to medical therapy did demonstrate benefit. In fact, they demonstrated a 15-mm Hg (on average) decrease in systolic blood pressure, indicating that before enrollment in the trial they probably were being treated as aggressively as they should be.

My take-home message is: If you have a patient with significant hypertension, make sure you’re implementing guideline-based therapies to bring their blood pressure into appropriate control. And if one is not successful in that case, then consider other options.

Dr. Bilazarian: One of the findings in the study was that at the end of the trial, there was a 2.5-mm Hg blood pressure difference between those with renal stenting and those without renal stenting (both on optimal medical therapy). Did that result surprise you?

Dr. Creager: It did surprise me for the very reason I just alluded to. I think that prior to enrollment in the trial, many of these patients who were treated with 2 or more antihypertensive drugs still might not have been treated aggressively enough with the right doses of these drugs or the right number of drugs to bring their blood pressure down.

In fact, I was pleased to see that an intensive medical regimen could be effective in these patients. And it sends another important message to our medical community that we can do more for these patients.

Dr. Bilazarian: You mentioned in this last answer that there may still be a role for identifying patients with renal artery stenosis. Can you help clarify that for me as a director of the vascular lab at Brigham and Women’s Hospital? As a teacher of postgraduate physicians, help me understand in what situation patients should be evaluated.

Currently, patients who may not have frank resistant hypertension get referrals to duplex ultrasound for assessment. Should that bar be moved up? Or is it only the most refractory patients who should be investigated? Or is it still valuable to know whether a patient has renal artery stenosis with noninvasive testing?

Dr. Creager: The bar does need to be moved without question. But there are several situations. I’ll give you 2 examples. One I mentioned: The patient who continues to have resistant hypertension despite aggressive medical therapy will be one such patient where I’ll be looking for secondary causes. And one of those secondary causes could be renal artery stenosis. So in that individual, duplex ultrasound would be appropriate, and if renal artery stenosis is found, continue the evaluation and treat that patient as the renal artery stenosis is confirmed.

Another example might be an individual who has recurrent acute pulmonary edema that cannot be explained by coronary artery disease or severe left ventricular dysfunction. That’s a patient I would consider working up for bilateral renal artery stenosis. And if found, I would treat. That patient population was really not the type that was included in the CORAL trial. So those are 2 examples.

Dr. Bilazarian: Our current guidelines say that there is a role for renal artery intervention for resistant hypertension, acute pulmonary edema, and declining renal function. It seems like the first of those has been taken off the table. Is there a role in the patient with declining renal function?

Dr. Creager: Well, that’s an important subset of patients, indeed. And I would be evaluating them for the potential causes of declining renal function. If they have renal artery stenosis, I would then initiate aggressive risk factor modification, antiplatelet therapy, and if they’re hypertensive, treat that as well.

But if in spite of that there still is evidence of declining renal function, then there’s a situation of someone who has failed medical therapy, and I would consider evaluating them for a renal artery stenosis. If one were to find, for example, bilateral renal artery stenosis in that patient or a severe stenosis to a single functioning kidney, then, yes, I would consider renal artery stenting in that individual.

Dr. Bilazarian: Great. Thank you for that summary on the trial called CORAL. Let’s move on to the second trial that you moderated. That trial is called ERASE, a study looking at supervised exercise therapy — an abbreviation I wasn’t familiar with: SET — supervised exercise therapy alone or supervised exercise therapy plus intervention of lower-extremity peripheral arterial disease. And that study was called ERASE. It built on an earlier study called CLEVER.[5] Please summarize the take-home message for the audience in that trial.

Dr. Creager: These were patients with peripheral artery disease and intermittent claudication, and the peripheral artery disease could have affected the aortoiliac system or the femoropopliteal system. The bottom line is that those patients who were randomized to both endovascular intervention and supervised exercise training had a much greater improvement in their walking time as assessed by treadmill testing, and also in quality of life as assessed by a number of instruments, compared with those patients who were just treated with supervised exercise training.

It adds incrementally to what we’ve previously understood. We know that supervised exercise training is extremely effective in improving walking time in patients with intermittent claudication. And as was shown with CLEVER, compared with medical therapy, endovascular intervention — at least in the aortoiliac area — is also associated with improvement in walking time.

So perhaps it’s no surprise that if you put the two together, they’re going to do better. And that’s what the ERASE trial showed.

Dr. Bilazarian: I agree with you. Many times, studies compare one or the other. And, of course, both is better than one or the other. I was happy to see that this trial looked at both.

There is one part of the trial that I had difficulty getting a take-home message from, and I’d love your input. As endovascular medicine physicians, we think in terms of the 3 zones of lower-extremity vascular disease: above the inguinal ligament, the fem-pop system, and then below the knee. Each becomes increasingly difficult, both for acute result as well as for durability. In this trial, half the patients had aortoiliac disease and half had fem-pop disease. Am I right to say that that might make it somewhat difficult to interpret whether the effects of supervised exercise therapy might be different for fem-pop disease or, say, aortoiliac disease, and that the bar for intervention might be lower for aortoiliac disease?

Dr. Creager: That’s a very important question. We don’t know yet what the subset analysis will be between those patients who had aortoiliac disease and underwent randomization and those who had femoropopliteal artery disease. And I’m sure we all await that analysis when it’s available.

Having said that, however, the studies show several things. It underscores the fact that no matter where the lesion is, patients still do better when exercise training is included in their therapeutic interventions. I think those of us who practice vascular medicine recognize the fact that endovascular intervention in the iliac arteries has been extremely successful and durable. And those patients really do benefit. d Our practice pattern and standard of care is to do endovascular intervention in patients with disabling claudication who have aortoiliac disease.

Superficial femoral artery disease, as you implied, is a little bit of a different situation. Those lesions are sometimes more difficult to treat and the durability is not as great. Within the context of this study, durability was pretty good in terms of restenosis. But I still think we need to see the subset analysis to make sure that those patients benefited as much as the entire group.

Dr. Bilazarian: Help us with a take-home message for US-based physicians. This was supervised exercise therapy in-home. We don’t have that available in the United States. Other than adding to our knowledge base, which is, of course, valuable, and being able to impart this knowledge to our patients and show them that this is of value, what other things can we do as a change in our practice to integrate this?

Dr. Creager: Currently we do need changes in healthcare policy, at least as it applies to supervised exercise training. We need reimbursement from CMS (Centers for Medicare & Medicaid Services). We need reimbursement from other third-party payers to provide additional incentive for physicians to recommend supervised exercise training for their patients. Unfortunately, that’s not available. And that’s one reason why patients in this country are not being referred for supervised exercise training. It’s an extremely effective intervention in patients with intermittent claudication.

Dr. Bilazarian: Great. Mark, thanks for joining me and for helping unpack these 2 trials for our audience: the ERASE trial of lower-extremity exercise in PAD patients, and the CORAL trial of renal artery stenting. I think they will add to our knowledge base and hopefully make practice changes in both areas. Thank you again for joining. And thank you for joining us for this program.



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Investigational Bioengineered Blood Vessel: Humacyte Presents Interim First-in-Human Data at the American Heart Association (AHA) Scientific Sessions 2013

Reporter: Aviva Lev-Ari, PhD, RN

The investigational bioengineered blood vessels represent a research and development milestone in vascular tissue engineering, as this technology could have the potential to help reduce or avoid surgical interventions and hospitalizations for patients with end-stage renal disease.

The Humacyte investigational bioengineered blood vessels are manufactured in a novel bioreactor system. The investigational bioengineered vessels go through a process of decellularization, which is designed to render them potentially non-immunogenic and implantable into any patient. These investigational bioengineered vessels are designed to be stored off-the-shelf for up to 12 months under standard refrigerated conditions, including, if successfully developedand approved,  on-site in hospitals.


Gail Thornton
Media Relations, Humacyte
1 908 392 3420 MOBILE

Jim Modica

West Mill Consulting



Humacyte Presents Interim First-in-Human Data

For Investigational Bioengineered Blood Vessel at the American Heart Association (AHA) Scientific Sessions 2013

  • The Humacyte investigational bioengineered blood vessel technology represents a research and development milestone in vascular tissue engineering.
  • Interim data from 28 patients in a three-center, first-in-human study in Poland indicate that all of the investigational blood vessels to date remain open to blood flow (patent), with no indication of an immune response in recipients, no aneurysms, and flow rates and durability suitable for dialysis.
  • The interim data suggest that the Humacyte investigational technology may have the potential to have high patency rates.
  • Longer follow-up and additional clinical studies will be required to confirm these preliminary observations.


RESEARCH TRIANGLE PARK, N.C., November 20, 2013 –Humacyte, Inc., a pioneer in regenerative medicine, today announced the presentation of interim, first-in-human data from an ongoing, multi-center study in Poland, evaluating the company’s investigational bioengineered blood vessel in hemodialysis patients with End-Stage Renal Disease (ESRD). The data were presented by Dr. Jeffrey H. Lawson, M.D., Ph.D., at the American Heart Association Scientific Sessions 2013 in Dallas, Texas (abstract). Dr. Lawson is Professor of Surgery and Pathology with tenure at Duke University Medical Center (Durham, North Carolina, USA), and Director of the Vascular Research Laboratory and Director of Clinical Trials for the Department of Surgery. He is also Clinical Consultant to Humacyte.

This is the first time surgical data from patients have been reported for the Humacyte investigational bioengineered vessel; the interim data come from a cohort of 28 study participants out of a total of 30 that will ultimately be enrolled in the three-site study in Poland (http://clinicaltrials.gov/show/NCT01744418%20CLN-PRO-V001%20NCT01744418). The first patients were implanted with the investigational vessels in December, 2012, and the vessels were first used for hemodialysis in February, 2013. The primary endpoints of the study in Poland are safety, tolerability, and patency to be examined at each visit within the first six months after graft implantation. Patients will be followed for an additional six months.

The interim patient data suggest that the Humacyte investigational bioengineered vessel may potentially be associated with low rates of vessel clotting, low infection rates, and low rates of surgical interventions. Low rates of clotting and intervention are consistent with preclinical data from animal testing that indicated little intimal hyperplasia. Preclinical data also indicated that, in animals, investigational vessels were remodeled to become living and more similar to native tissue. To date in the Polish study, the investigational vessel has remained open to blood flow (patent), with no indication of an immune response in recipients, no aneurysms (abnormal widening or ballooning of part of an artery due to weakness in the blood vessel wall), and flow rates and durability suitable for dialysis. Longer follow-up and additional clinical studies will be required to confirm these preliminary observations.

Co-authors on the presentation were: Drs. Marek Iłżecki, Tomasz Jakimowicz, Alison Pilgrim, Stanisław Przywara, Jacek Szmidt, Jakub Turek, Wojciech Witkiewicz, Norbert Zapotoczny, Tomasz Zubilewicz, and Laura Niklason.

Described by Investigator as “Breakthrough Investigational Technology”

“Based on our experience to date, this is breakthrough investigational technology,” said Principal Investigator Prof. Tomasz Zubilewicz, M.D., Ph.D., head, Department of Vascular Surgery and Angiology, Medical University of Lublin, Poland. “The investigational bioengineered vessel seems like it could have the potential to be shown to be superior to synthetic grafts in vascular access for hemodialysis in all aspects. This technology also has potential for other areas of vascular surgery, including replacement of infected synthetic grafts.”

“We are very encouraged by the Humacyte investigational bioengineered vessel’s performance in end-stage renal disease patients,” said Dr. Lawson. “Tremendous medical need exists for vascular access grafts in patients with ESRD who require dialysis. Based on this interim data and other ongoing research, we believe that the investigational bioengineered vessel has potential to meet this significant need.”

Need to Overcome Limitations of PTFE Grafts

Currently available synthetic vessels made from polytetrafluoroethylene (PTFE) are subject to many complications and about half fail within a year, requiring replacement surgery. PTFE vessels tend to become blocked (have low patency rates), have high rates of stenosis (an abnormal narrowing in a blood vessel that can be associated with hemodialysis), and high intervention rates.

“We continue to make significant progress in our research and development program with the Humacyte investigational bioengineered blood vessel,” said Laura E. Niklason, M.D., Ph.D., professor and vice chair of Anesthesia, professor of Biomedical Engineering, Yale University, and founder, Humacyte. “With our current interim study data, all of the Humacyte vessels have remained open to blood flow, with 20 out of the 28 implants requiring no intervention to date. We are grateful to patients, investigators, regulators and the broader vascular community for their ongoing collaboration and support in advancing this science.”

Unmet Medical Need in Chronic Kidney Disease

The Humacyte investigational technology is being developed with the goal of pursuing approval for use in patients with chronic kidney disease, a major global health problem affecting 26 million Americans[i] and around 40 million people in the European Union (EU).[ii] Individuals who progress to end-stage renal disease (ESRD) require renal replacement therapy (hemodialysis or kidney transplant); more than 380,000 patients currently require hemodialysis in the U.S.[iii] and some 250,000 patients require hemodialysis or have had kidney transplants in the EU.[iv] The investigational bioengineered vessels, if successfully developed and approved for use in ESRD by regulatory authorities, could offer the potential for significant cost savings to the healthcare system. These investigational bioengineered vessels represent a research and development milestone in vascular tissue engineering, as this technology could have the potential to help reduce or avoid surgical interventions and hospitalizations for patients with ESRD.

Investigators Highlight Preliminary Experiences In Patients

The investigators involved with the study in Poland cited their clinical observations in connection with the release of the preliminary patient data obtained for the Humacyte investigational technology.

“It was an exciting experience to be involved with this study, and to participate in this potential breakthrough in vascular surgery. This investigational bioengineered vein is a promising development for vascular surgeons,” said Principal Investigator Prof. Jacek Szmidt, head of the Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Poland.

“The Humacyte investigational bioengineered vessel was very easy to handle during implantation in this study. The graft maintained excellent mechanical properties, and based on our team’s experience, the complication rate to date has been very low compared with synthetic grafts,” said Investigator Stanisław Przywara, M.D., Ph.D., senior assistant, Department of Vascular Surgery and Angiology, Medical University of Lublin, Poland.

“During implantation in this study, the Humacyte investigational vessel behaved very much like a native vein.  Anastomotic hemostasis was achieved almost immediately. Insertion of needles to perform hemodialysis was easy and as reported by our nephrologists, provides very good adequacy of hemodialysis,” said Investigator Marek Iłżecki, M.D., Ph.D., senior resident, Department of Vascular Surgery and Angiology, Medical University of Lublin, Poland.

U.S. Clinical Trial Started in May, 2013

A multi-center U.S. clinical trial began in May, 2013 under a U.S. Investigational New Drug (IND) application. The U.S. trial will involve up to 20 patients across three sites to assess safety and performance of the innovative, investigational bioengineered blood vessels to provide vascular access for hemodialysis in ESRD patients.

About the Investigational Bioengineered Blood Vessels

The Humacyte investigational bioengineered blood vessels are manufactured in a novel bioreactor system. The investigational bioengineered vessels go through a process of decellularization, which is designed to render them potentially non-immunogenic and implantable into any patient. These investigational bioengineered vessels are designed to be stored off-the-shelf for up to 12 months under standard refrigerated conditions, including, if successfully developed and approved,  on-site in hospitals. Subject to receipt of regulatory approval, these properties could make the investigational bioengineered vessels readily available to surgeons and patients, and could eliminate the wait for vessel production or shipping. Data from studies of the investigational bioengineered vessels in large animal models reflect resistance to thickening for up to one year, and the early human studies that are now underway will provide safety and performance data in patients to support a future application for regulatory approval.

About Humacyte

Humacyte, Inc., a privately held company founded in 2005, is a medical research, discovery and development company with clinical and pre-clinical stage investigational products. Humacyte is primarily focused on developing and commercializing a proprietary novel technology based on human tissue-based products for key applications in regenerative medicine and vascular surgery. The company uses its innovative, proprietary platform technology to engineer human, extracellular matrix-based tissues that are designed be shaped into tubes, sheets, or particulate conformations, with properties similar to native tissues. These are being developed for potential use in many specific applications, with the goal to significantly improve treatment outcomes for a variety of patients, including those with vascular disease and those requiring hemodialysis. The company’s proprietary technologies are designed to result in off-the-shelf products that, once approved, can be utilized in any patient. The company web site is www.humacyte.com.

Forward-Looking Statement

Information in this news release contains “forward-looking statements” about Humacyte. These statements, including statements regarding management’s projections relating to future results and operations, are based on, among other things, management’s views, assumptions and estimates, developed in good faith, all of which are subject to known and unknown factors that may cause actual results, performance or achievements, or industry results, to differ materially from those expressed or implied by such forward-looking statements.





From: Gail Thornton <gail@westmillconsulting.com>
Reply-To: Gail Thornton <gail@westmillconsulting.com>
Date: Wed, 20 Nov 2013 09:24:32 -0800 (PST)
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: Re: American Heart Association: Humacyte Investigational Bioengineered Blood Vessels

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Echocardiogram Quantification: Quest for Reproducibility and Dependability

Reporter: Aviva Lev-Ari, PhD, RN

How can echo quantification become more reproducible and dependable?

 Senior Director, Global Cardiology at Innovations in Cardiology

Innovations in Cardiology

a subgroup of Innovations In Health on LinkedIn.com

Echocardiography encompasses an array of clinically important tasks including quantifying cardiac chamber size, ventricular mass and function.

Based on your experience, how can echo quantification become more reproducible and dependable?

Comments made by Group members:


Yoni TiroshYoni

Yoni Tirosh

CEO at M.I. Medical Incentive Ltd.

Hello Ivan,
I’ve sent you a personal message regarding an innovative development related to Echo use.


Tim ZepickTim

Tim Zepick

Office Manager; Technical Director, Ultrasound at Line Medical

It’s impossible.

There are large variations in quality of ultrasound systems. There are also large variations in skill levels of operators. And those skill levels change over time. But the most detrimental factor is that the human body is a dynamic and unique system. Some subjects are technically difficult and LV function is basically impossible to assess, even with an excellent US system. Measurement of LVPWiD is a guess on these patients. Then there are subjects on whom you can obtain excellent images at intercostal space #2, #3, and #4. And the anatomy is bisected at a different angle and might yield three different measurements at each approach. The same can be said for a lot of the 2-D length measurements. I can probably make your RA five centimeters wide, if I try.

That said, doing about 5,000 studies will get you pretty good at recognizing your limitations, realizing the need to remeasure erroneous data, common failings of ultrasound physics and other sources of error.

Thankfully, inexperienced techs get a good education on spotting and evaluating the “exciting” stuff because these nuanced stuff takes time to develop.


Wayne PetersonWayne

Wayne Peterson

Product Manager

As a former Philips employee, hello. My clinical skills included cardiac ultrasound. In response to your question, a software program with edge resolution enhancement and auto analysis would be amazing. It would remove user variability.


Tony GallagherTony

Tony Gallagher

Clinical Coordinator of Cardiology and Cardio-Pulmonary Rehabilitation at Floyd Medical Center

I agree with Tim that it is not possible. In deference to Wayne; edge recognition software would help. But the variety of equipment skill levels, even peoples varied vision; prevent 100% agreement.

Even at the larger conferences, when you attend the “read with the experts” courses, you see that they tend to disagree looking at the same images.

unless equipment, education, and criteria for performing studies gets standardized; not going to happen.


Alberto GomezAlberto

Alberto Gomez

Research Assistant at King’s College London

Reproducibility and reduction (I.e. not complete removal) of variability could be achieved in several ways. For example, to cite a few: multi view imaging to remove view dependency on edge definition and occlusion; angle independent flow quantification using 3D color Doppler; image fusion and compounding with tracked probes; simultaneous (or quasi-simultaneous) multi-prove systems. All these are engineering and research challenges but we will get to them. How long it will take highly depends on how willing manufacturers are to open up to research institutions and how willing research institutions are to share and exploit results.


Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN

Cardiovascular Original Research: Curation Methodology Designer at Leaders in Pharmaceutical Business Intelligence

Please visit us

On right hand side Categories, pl. Click on Medical Imaging
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Justin Pearlman, MD, PhD, FACC

Thank you
Aviva Lev-Ari, PhD, RN


Clifford ThorntonClifford

Clifford Thornton

Echocardiography Technician at CapitalHealth

You’re a very brave man Ivan, asking the holy grail question of echocardiography! I’ve been doing echoes at prominent institutions for 10 years, been registered in echo since 2006, have performed probably more than 6,000 adult echoes, teach echo to technicians and sometimes residents, attended echo related conferences and read the latest Dr. Feigenbaum and Dr. Otto textbooks – so I can speak to this topic.

Here’s the deal. From what I understand, the best echo has to offer as far as EF quantification (which I think is usually the focus) is 3D volume quantification. The problem is, is that primarily due to reimbursement issues this technology has had very slow adoption and application and therefore low availability. A great application of this technology would be evaluating a patient for possible LVAD placement/treatment or heart transplant.

Given this, what most technicians are left with is 2 Dimensional echo. There are many ways we can measure Ejection Fraction with 2D Echo and they include direct 2D measurement (measuring the left ventricular internal dimension at end-diastole (LVIDd) and the left ventricular internal dimension at end-systole (LVIDs). Most modern echo systems have very specific packages that enable fairly easy measurements of these aspects of the heart and are clearly labeled. A technician can also make a similar measurement using M-Mode. The achilles-heel of M-Mode based measurement of EF is that the picture or the heart in the picture (from the parasternal long-axis window/view – PLAX) must be on-axis. If the picture is off-axis, your direct 2D measurements should be more accurate. Side note: this all goes out the window with a poorly trained or lazy echo tech who has little to no idea of what they’re doing – and unfortunately there’s too many of these out there (read more on this later). So, as far as 2D left ventricular dimension measurements of EF go, direct 2D (on screen) measurements are preferable.

According to a Wake Forest Cardiology conference which I attended several years ago in Orlando, “The Beat Goes On” the best or most accurate measurement of EF with 2D echo (assuming there’s a good, well-trained, knowledgeable and hard working echo tech performing the test) is with Simpson’s Bi-plane method/Quantification. This measurement is based on volume of blood in the heart at end-diastole and end-systole (see the pattern). Once this is calculated a technician can then calculate the stroke volume (which most packages calculate automatically once the proper measurements are calculated and entered) and the cardiac output (Stroke volume (SV) X heart rate (HR)). As a reference the heart wants to push around 5 liters of blood per minute to sustain life and normal body function. Of course this can greatly increase with exercise or decrease slightly with rest as can your respiratory function.

The way the Biplane Simpsons’ method is performed is that a technician calculates the following from both the apical-4-chamber view and the apical-2-chamber view (again most modern systems have these measurements built into the package and labeled and they can also be exported directly to the preliminary report through DICOM specs.):
1. Left ventricular volume at End-Diastole (LVVED) – A4C

1. Left ventricular volume at End-Systole (LVVES) – A4C

1. Left ventricular volume at End-Diastole (LVVED) – A2C

1. Left ventricular volume at End-Systole (LVVED) – A2C

Yes, you can imagine this is very time consuming. It can be done later once the scan is done however once the patient leaves, you can not go back and adjust your view if you think your picture is foreshortened or off-axis, etc.

Please see very relevant document to this topic from the American Society of Echocardiography, Committee Recommendations:


Clifford ThorntonClifford

Clifford Thornton

Echocardiography Technician at CapitalHealth

The bottom line is that quantification in echo, particularly in calculating EF depends on the situation. Simpsons’ method is not performed routinely in most labs because if the EF visually looks normal (around 55% – 70%) from the long-axis, short-axis and apical 4 chamber and apical 2 chamber views then there’s usually not a huge need for it; little additional benefit. I try to do it as much as possible because I like to do as best an echo I can and also it’s good to practice and a little fun when you have very clear/great quality pictures (ironically these are the people who you know their EF is probably normal the minute they walk through your door!).

There are many tools and techniques one can employ to optimize their 2D/Simpsons’ EF measurements. Here are a few:
* the patient into the proper position (left lateral decubitus) — I use a wedge to keep them on their left side and keep their head well supported with a rolled up pillow or rolled up blankets

* the proper echo settings/frequency. Use penetration setting if you have to, but if they have good pictures, use the best resolution setting you can without sacrificing endocardial border definition — otherwise you’re defeating the purpose

* the proper breathing techniques (I find from parasternal window it’s best to have the patient inhale, exhale all the way and then hold their breath for loop acquisition and best to have them inhale and hold for apical acquisitions – but just play around with it until you get the picture you want).

* the picture on axis and avoid foreshortening — this is very key for the Simpsons’ method of discs

Now, you’ve tried all this, you’re sweating, your hand and shoulder are about to fall off, you see stars or angels or both and the patient and their family think you are completely clueless and think you’re torturing their Wife/Husband/Daughter/Friend/etc. and you’re wondering if you’ll have a job tomorrow. So what do you do?

Definity Echo contrast (Perflutren Lipid Microsphere) – http://www.definityimaging.com/ – you say? Yes, possibly. You need to A. Get the patient’s consent (although this is beginning to change) B. Establish IV access for the injection of the Definity solution C. Activate the Definity and use it within a certain period D. Utilize it correctly.

Basically Definity contrast is little gas bubbles that reflect the ultrasound beams (for which 2D pictures are generated from pulsed-wave doppler) very well or strongly and allow for a stronger, clearer/better resolution image. The heart walls/endocardial borders are one color and the contrast is the other (the contrast is usually the white-milky substance you see inside the left ventricle while it’s filling and contracting. Most people think it’s pretty “cool” when they see it and it can make a dramatic difference in how you visually estimate or calculate the EF. As I mentioned, Simpsons’ method (the preferred 2D EF calc. method) is highly dependent on operator skill and effort and hence picture quality. And Definity contrast can greatly enhance the picture quality. Last week I had a patient where you could barely see any endocardial border without Definity and visually estimating his EF would be a total shot in the dark. Well, we administered Definity, and I’m not lying it was still a tough scan, but once the Definity was injected and began to appear in the right ventricle and then left, I could see immediately that his EF was completely normal (55-60%). This was important to assess clinically because the patient was in the CCU at the time and he was s/p CABG. Judging whether the EF is normal or not can have a big play in clinical decision making for other conditions.

Ironically getting an accurate EF has to do more with having the right technician perform your test than it has to do with technology or anything else. And unfortunately there’s no lack of pitfalls there.



Reza Mehzad, MD, MPH

Mercy Heart Institute

Full automation for 3D echocardiography volume assessment AND having a safe contrast agents to be used with all echo studies.

 Clifford Thornton likes this

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Comment by Cardiologists posted on LinkedIn’s

European Cardiovascular Medical Devices Group, a subgroup of Cardiovascular Medical Devices Group

on Stenting for Proximal LAD Lesions: In Reference to the Invasive Procedure performed on former President George W. Bush

UPDATED on 8/7/2018

Long-Term Outcomes of Stenting the Proximal LAD

Study Questions:

What are the outcomes of patients undergoing drug-eluting stent (DES) implantation according to lesion location within or outside the proximal left anterior descending (LAD) artery?


Among the 8,709 patients enrolled in PROTECT (Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial), a multicenter percutaneous coronary intervention (PCI) trial, the investigators compared the outcomes of 2,534 patients (29.1%; 3,871 lesions [31.5%]) with stents implanted in the proximal LAD with 6,172 patients (70.9%; 8,419 lesions [68.5%]) with stents implanted outside the proximal LAD. For each event, a multivariate model was constructed that examined the effect of several individual baseline clinical and angiographic characteristics, including proximal LAD target lesion, on outcomes (i.e., MACE [major adverse cardiac events], target vessel failure [TVF], and myocardial infarction [MI]).


At 4-year follow-up, death rates were the same (5.8% vs. 5.8%; p > 0.999), but more MIs occurred in the proximal LAD group (6.2% vs. 4.9%; p = 0.015). The rates of clinically driven TVF (14.8% vs. 13.5%; p = 0.109), MACE (15.0% vs. 13.7%; hazard ratio, 1.1; 95% CI, 0.97-1.31; p = 0.139), and stent thrombosis (2.1% vs. 2.0%; p = 0.800) were similar. DES type had no interaction with MACE or TVF. In multivariate analysis, the proximal LAD was a predictor for MI (p = 0.038), but not for TVF (p = 0.149) or MACE (p = 0.069).


The authors concluded that proximal LAD location was associated with higher rates of MI during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE.


This post hoc analysis of a prospective, multicenter study reports no difference in the rates of death, MACE, or TVF at 4 years according to intervention at a proximal LAD or nonproximal LAD lesion. The occurrence of the predefined primary endpoint of stent thrombosis was also not dependent on whether a proximal LAD or nonproximal LAD site was treated. However, of note, stenting of proximal LAD lesions was associated with significantly higher rates of MI compared with stenting of nonproximal LAD lesions. Overall, these findings appear to suggest that proximal LAD lesions may not have additional risk in the contemporary DES era, but the higher risk of MI needs to be studied further. Future studies should compare longer-term clinical outcomes between proximal LAD PCI with DES and minimally invasive left internal mammary artery to LAD.




Stenting for Proximal LAD Lesions

Curator: Aviva Lev-Ari, PhD, RN

Michael Reinhardt • First, the media really should not be calling this “stent surgery” its a stent procedure just ask any post-CABG patient… Anyway it really is not possible to determine whether or not is was “unnecessary” without all the relevant patient data; which coronary vessel(s) involved, percent stenosis, etc. Actually I find it interesting that they apparently decided to stent the former president on the basis of a CT Angiogram which is not the standard of care for coronary imaging. I have to assume they performed an additional testing like a CT perfusion analysis and saw a clinically relevant defect and this support the decision to stent. Regarding the post-stent drugs cloplidigrel is not a benign drug but benefits far outweigh the downside of a sub-acute thrombosis which might result in a more serious future event = acute MI.

Rafael Beyar • This was absolutely an indicated procedure and almost all rational physician will treat a young patient with proximal LAD lesions with either a stent or bypass surgery

Dov V Shimon MD • No doubt! Proximal (‘close to origin’) LAD lesions are the leading “Widow makers”. Reestablishing of flow in the artery is saving from cardiac damage and death. Drug eluting stent have 2nd and 3rd generations with very low and acceptable reclosure rates and almost no abrupt closure (thrombosis). True, CTA is a screening test, but it astablishes the need for diagnostic and therapeutic angiogram. We, heart surgeons can provide long-term patency to the LAD using LIMA arterial bypass. The current advantage of stent is the incovenience and pain of surgery. Any responsible physician would opt the procedure even for himself, his relatives , his patients and for definitely for GW Bush.


Coronary anatomy and anomalies

On the left an overview of the coronary arteries in the anterior projection.

Coronary anatomy and anomalies

RCA, LAD and Cx in the anterior projection

On the left an overview of the coronary arteries in the lateral projection.

  • Left Main or left coronary artery (LCA)
    • Left anterior descending (LAD)
      • diagonal branches (D1, D2)
      • septal branches
    • Circumflex (Cx)
      • Marginal branches (M1,M2)
  • Right coronary artery
    • Acute marginal branch (AM)
    • AV node branch
    • Posterior descending artery (PDA)

Eur J Cardiothorac Surg. 2004 Apr;25(4):567-71.

Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?


Thoraxcentre, Groningen University Hospital, Groningen, The Netherlands.



The objective of this study was to compare the long-term outcome of patients with an isolated high-grade stenosis of the left anterior descending (LAD) coronary artery randomized to percutaneous transluminal coronary angioplasty with stenting (PCI, stenting) or to off-pump coronary artery bypass grafting (surgery).


Patients with an isolated high-grade stenosis (American College of Cardiology/American Heart Association classification type B2/C) of the proximal LAD were randomly assigned to stenting (n=51) or to surgery (n=51) and were followed for 3-5 years (mean 4 years). Primary composite endpoint was freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiac death, myocardial infarction, stroke and repeat target vessel revascularization. Secondary endpoints were angina pectoris status and need for anti-anginal medication at follow-up. Analysis was by intention to treat.


MACCEs occurred in 27.5% after stenting and 9.8% after surgery (P=0.02; absolute risk reduction 17.7%). Freedom from angina pectoris was 67% after stenting and 85% after surgery (P=0.036). Need for anti-anginal medication was significantly lower after surgery compared to stenting (P=0.002).


Patients with an isolated high-grade lesion of the proximal LAD have a significantly better 4-year clinical outcome after off-pump coronary bypass grafting than after PCI.

Daily Dose

08/12/2013 | 5:48 PM

Was George Bush’s stent surgery really unnecessary?

By Deborah Kotz / Globe Staff


Ever since President George W. Bush had stent surgery last Tuesday to open a blocked artery, leading physicians who weren’t involved in his care have wondered publically why he had this “unnecessary” procedure. Large clinical trials have demonstrated that stent placement doesn’t extend lives or prevent a future heart attack or stroke in those with stable heart disease.

What’s more, Bush could wind up with complications like a reblockage where the stent was placed or excessive bruising or internal bleeding from the blood thinners that he must take likely for the next year.

Dr Richard Besser, the chief medical correspondent for ABC News, questioned why Bush had an exercise stress test as part of his routine physical exam given that he had no symptoms like chest pain or shortness of breath. The stress test indicated signs of an artery blockage.

“In people who are not having symptoms, the American Heart Association says you should not do a stress test,” Besser said, “since the value of opening that artery is to relieve the symptoms.”

Cleveland Clinic cardiologist Dr. Steve Nissen agreed in his interview with USA Today. Bush, he said, likely “got the classical thing that happens to VIP patients, when they get so-called executive physicals and they get a lot of tests that aren’t indicated. This is American medicine at its worst.”

Two physicians wrote in an Washington Post op-ed column titled “President Bush’s unnecessary surgery” that they worry that the media coverage of Bush’s stent will lead “patients to pressure their own doctors for unwarranted and excessive care.”

But none of these doctors actually treated Bush or examined his medical records, so I’m a little surprised they’re making such firm calls.

Bush, an avid biker who recently completed a 100-kilometer ride, probably shouldn’t have had the exercise stress test if he wasn’t having any heart symptoms. “Routine stress testing used to be done 20 years ago, but isn’t recommended any longer since it doesn’t have any benefit,” said Brigham and Women’s cardiologist Dr. Christopher Cannon.

But Bush’s spokesman insisted the stent was necessary after followup heart imaging via a CT angiogram “confirmed a blockage that required opening.”

Cannon said Bush’s doctors may have seen signs that blood flow wasn’t getting to a significant part of the heart muscle, a condition known as ischemia. Researchers have found that those with moderate to severe ischemia appear to experience a reduction in fatal heart attacks when they have a stent placement along with medical therapy, rather than just taking medications alone. (Larger studies, though, are needed to confirm this finding.)

“If a blockage occurs at the very start of the artery and it’s extensive—95 percent blocked—then chances are it will cause significant ischemia,” Cannon said. While severe ischemia usually causes light-headedness or dizziness during exercise, Bush may have had more moderate ischemia that didn’t cause such symptoms.

It’s impossible to know for certain, he added, without seeing his medical records firsthand.


President Bush’s unnecessary heart surgery

  • By Vinay Prasad and Adam Cifu, Published: August 9

Vinay Prasad is chief fellow of medical oncology at the National Cancer Institute and the National Institutes of Health. Adam Cifu is a professor of medicine at the University of Chicago.

Former president George W. Bush, widely regarded as a model of physical fitness, received a coronary artery stent on Tuesday. Few facts are known about the case, but what is known suggests the procedure was unnecessary.

Before he underwent his annual physical, Mr. Bush reportedly had no symptoms. Quite the opposite: His exercise tolerance was astonishing for his age, 67. He rode more than 30 miles in the heat on a bike ride for veterans injured in the wars in Iraq and Afghanistan.

If Mr. Bush had visited a general internist practicing sound, evidence-based care, he would not have had cardiac testing. Instead, the doctor would have had conducted age-appropriate cancer screening. For the former president, this would include only colon cancer screening. It no longer would include even prostate-specific antigen testing for cancer. The doctor would have screened for cholesterol, checked for hypertension and made sure the patient was up to date on age-appropriate vaccinations, including those for pneumococcal pneumonia and shingles. Presumably Mr. Bush got these things, and he got the cardiac test as well.What value does a stress test add for an otherwise healthy 67-year-old?No study has shown that this examination improves outcomes. The trials that have been done for so-called routine stress testing examined higher-risk patients. They found that performing stress tests on people at high risk of cardiovascular disease may detect blockages but does not improve symptoms or survival. Routine stress testing does, however, increase the use of procedures such as coronary stenting.Unfortunately, Mr. Bush, like many VIPs, may be paying the price of these in-depth investigations. His stress test revealed an abnormality, prompting another test: a CT angiogram. This study showed a blockage, which was stented open during an invasive procedure. It is worth noting that at least two large randomized trials show that stenting these sorts of lesions does not improve survival. Because Mr. Bush had no symptoms, it is impossible that he felt better after these procedures.

Instead, George W. Bush will have to take two blood thinners, aspirin and Plavix, for at least a month and probably a year. (The amount of time a blood thinner is needed depends on the type of stent placed). While he takes these medications, he will have a higher risk of bleeding complications with no real benefit.

Although this may seem like an issue important only to the former president, consider the following: Although the price of excessive screening of so-called VIPs is usually paid for privately, follow-up tests, only “necessary” because of the initial unnecessary screening test, are usually paid for by Medicare, further stressing our health-care system. The media coverage of interventions like Mr. Bush’s also leads patients to pressure their own doctors for unwarranted and excessive care.


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Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Curator: Aviva Lev-Ari, PhD, RN

This article is Part VI in a Series of articles on Calcium Release Mechanism, the series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP


Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN


Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN


Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN


Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN


Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part IXCalcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP


Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


This article has THREE parts:

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

The following two discoveries in Cardiac Gene Therapies represent the FRONTIER IN CARDIOLOGY for 2012 – 2013: Solution Advancement for Improving Myocardial Contractility

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Roger J. Hajjar, MD, a pioneering Mount Sinai researcher who has published cutting-edge studies on heart failure, has been named the recipient of the 2013 BCVS Distinguished Achievement Award by theAmerican Heart Association and the Council on Basic Cardiovascular Sciences. Dr. Hajjar, who is The Arthur and Janet C. Ross Professor of Medicine and Director of The Helmsley Trust Translational Research Center, will be honored at the American Heart Association’s Scientific Sessions Annual Conference later this year.

“Dr. Hajjar will receive the award for his groundbreaking contributions to developing gene therapy treatments for cardiac disease,” says Joshua Hare, MD, who is President-elect of the Council on Basic Cardiovascular Sciences. He will also be recognized for his work on behalf of the Council.

Over the years, Dr. Hajjar’s laboratory has made important basic science discoveries that were translated into clinical trials. Most recently, Dr. Hajjar and his researchers identified a possible new drug target for treating or preventing heart failure. Says Mark A. Sussman, PhD, a former president of the Council, “Dr. Hajjar was among the first, and certainly the most successful, in combining gene therapy and treatment of heart failure. He shows a relentless pursuit of translating basic science into real-world treatment of heart disease.”

This article was first published in Inside Mount Sinai.


John Hopkins, Distinguished Alumnus Award 2011

Roger J. Hajjar, Engr ’86
Dr. Roger Hajjar received his bachelor’s degree in biomedical engineering from Johns Hopkins University in 1986. A cardiologist and translational scientist, he is a leader in gene therapy techniques and model testing for cardiovascular diseases. Dr. Hajjar is professor of medicine and cardiology, and professor of gene and cell medicine at Mount Sinai Medical Center in New York, as well as research director of Mount Sinai’s Wiener Family Cardiovascular Research Laboratories. Dr. Hajjar was recruited to Mt. Sinai from Harvard Medical School where he was assistant professor of medicine and staff cardiologist in the Heart Failure & Cardiac Transplantation Center. He received his medical degree from Harvard Medical School and trained in internal medicine and cardiology at Massachusetts General Hospital in Boston. Dr. Hajjar has concentrated his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques in the heart to improve contractility. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis. Dr. Hajjar has significant expertise in gene therapy. In 1996, he won the Young Investigator Award of the American Heart Association (Council on Circulation). In 1999, Dr. Hajjar was awarded the prestigious Doris Duke Clinical Scientist award and won first prize at the Astra Zeneca Young Investigator Forum. Dr. Hajjar holds a number of NIH grants.


Dr Hajjar is the Director of the Cardiovascular Research Center, and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai School of Medicine, New York, NY. He received his BS in Biomedical Engineering from Johns Hopkins University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences & Technology. He completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Dr. Hajjar is an internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr Hajjar’s research has been recognized with the initiation and recent successful completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance.

Prior to joining Mount Sinai, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital.

Dr. Hajjar has won numerous awards and distinctions, including the Young Investigator Award of the American Heart Association. He was awarded a Doris Duke Clinical Scientist award and has won first prize at the Astra Zeneca Young Investigator Forum. He is a member of the American Society for Clinical Investigation. He was recently awarded the Distinguished Alumnus Award from Johns Hopkins University and the Mount Sinai Dean’s award for Excellence in Translational Science. He has authored over 260 peer-reviewed publications.


Meet the Director of Mount Sinai’s Cardiovascular Research Center

“Cardiovascular diseases are the number one cause of death globally. In order to tackle them in all aspects, we must unite improved diagnostic techniques with more refined therapies.”

Roger J. Hajjar, MD, Director of the Cardiovascular Research Center, the Arthur & Janet C. Ross Professor of Medicine, Professor of Gene & Cell Medicine, Director of the Cardiology Fellowship Program, and Co-Director of the Transatlantic Cardiovascular Research Center, which combines Mount Sinai Cardiology Laboratories with those of the Universite de Paris – Madame Curie.

In the late 1990s, the possibility that discoveries in genetics and genomics could have a positive impact on the diagnosis, treatment, and prevention of cardiovascular diseases seemed to be just a distant promise. Today, a little more than a decade later, the promise is beginning to take shape. Roger J. Hajjar, MD and his multidisciplinary team of investigators are beginning to translate scientific findings into real therapies for cardiovascular diseases. As Director of the Cardiovascular Research Institute and a cardiologist by training, Dr. Hajjar guides the growth of a cutting-edge translational research laboratory, which is positioning Mount Sinai as the leader in cardiovascular genomics.

An internationally recognized scientific leader in the field of cardiac gene therapy for heart failure, Dr. Hajjar is expanding studies of the basic mechanisms of cardiac diseases and identification of high-risk groups and genomic predictors so that they can be part of the daily clinical care of patients. Unique biorepositories combined with cardiovascular areas of excellence across Mount Sinai make possible crucial genetic studies.

First Gene Therapy for Heart Failure

Under Dr. Hajjar’s leadership, the Cardiovascular Research Center has already developed the world’s first potential gene therapy for heart failure. Known as AAV1.SERCA2a, this therapy actually revives heart tissue that has stopped working properly. It has led to new treatment possibilities for patients with advanced heart failure, whose options used to be severely limited. The significance of this research has been recognized with the initiation and successful completion Phase 1 and Phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure. Phase 3 validation begins in 2011.

The Cardiovascular Research Center’s next research projects, already underway, focus on using novel gene therapy vectors to target diastolic heart failure, ventricular arrhythmias, pulmonary hypertension, and myocardial infarctions.

In addition to targeting signaling pathways to aid failing heart cells, ongoing work at the Cardiovascular Research Center involves studying how to block signaling pathways in cardiac hypertrophy as well as apoptosis. The laboratory team is also targeting a number of signaling pathways in the aging heart to improve dystolic function.

Prior to joining Mount Sinai in 2007, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital. After earning a bachelors of science degree in Biomedical Engineering from Johns Hopkins University and a medical degree from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology, he completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Scientific Advisors

Roger J. Hajjar, MD, Co-Founder and a Scientific Advisor of Celladon Co, plans to commercialize AAV1.SERCA2a for the treatment of heart failure.
Dr. Roger J. Hajjar is the Director of the Cardiovascular Research Center at the Mt. Sinai School of Medicine. Previously, he was the Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has an active basic science laboratory and concentrates his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques targeting the heart as a therapeutic modality to improve contractility in heart failure. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis.

Gene Therapy: Volume 19, Issue 6 (June 2012)

Special Issue: Cardiovascular Gene Therapy

Guest Editor

Roger J Hajjar MD, Mount Sinai School of Medicine, New York, NY Director, Cardiovascular Research Institute, Arthur & Janet C Ross Professor of Medicine

SDF-1 in myocardial repair  

M S Penn, J Pastore, T Miller and R Aras

Gene Ther 19: 583-587; doi:10.1038/gt.2012.32

Abstract | Full Text | PDF

Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?  

R A Li

Gene Ther 19: 588-595; doi:10.1038/gt.2012.33

Abstract | Full Text | PDF

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy  

J-S Hulot, G Senyei and R J Hajjar

Gene Ther 19: 596-599; advance online publication, May 17, 2012; doi:10.1038/gt.2012.34

Abstract | Full Text | PDF

Gene therapy for ventricular tachyarrhythmias  

J K Donahue

Gene Ther 19: 600-605; advance online publication, April 26, 2012; doi:10.1038/gt.2012.35

Abstract | Full Text | PDF

Prospects for gene transfer for clinical heart failure  

T Tang, M H Gao and H Kirk Hammond

Gene Ther 19: 606-612; advance online publication, April 26, 2012; doi:10.1038/gt.2012.36

Abstract | Full Text | PDF

Targeting S100A1 in heart failure  

J Ritterhoff and P Most

Gene Ther 19: 613-621; advance online publication, February 16, 2012; doi:10.1038/gt.2012.8

Abstract | Full Text | PDF

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond  

M Giacca and S Zacchigna

Gene Ther 19: 622-629; advance online publication, March 1, 2012; doi:10.1038/gt.2012.17

Abstract | Full Text | PDF

Vein graft failure: current clinical practice and potential for gene therapeutics  

S Wan, S J George, C Berry and A H Baker

Gene Ther 19: 630-636; advance online publication, March 29, 2012; doi:10.1038/gt.2012.29

Abstract | Full Text | PDF

Percutaneous methods of vector delivery in preclinical models  

D Ladage, K Ishikawa, L Tilemann, J Müller-Ehmsen and Y Kawase

Gene Ther 19: 637-641; advance online publication, March 15, 2012; doi:10.1038/gt.2012.14

Abstract | Full Text | PDF

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function  

E Di Pasquale, M V G Latronico, G S Jotti and G Condorelli

Gene Ther 19: 642-648; advance online publication, March 1, 2012; doi:10.1038/gt.2012.19

Abstract | Full Text | PDF

Intracellular transport of recombinant adeno-associated virus vectors  

M Nonnenmacher and T Weber

Gene Ther 19: 649-658; advance online publication, February 23, 2012; doi:10.1038/gt.2012.6

Abstract | Full Text | PDF

Gene delivery technologies for cardiac applications  

M G Katz, A S Fargnoli, L A Pritchette and C R Bridges

Gene Ther 19: 659-669; advance online publication, March 15, 2012; doi:10.1038/gt.2012.11

Abstract | Full Text | PDF

Cardiac gene therapy in large animals: bridge from bench to bedside  

K Ishikawa, L Tilemann, D Ladage, J Aguero, L Leonardson, K Fish and Y Kawase

Gene Ther 19: 670-677; advance online publication, February 2, 2012; doi:10.1038/gt.2012.3

Abstract | Full Text | PDF

Progress in gene therapy of dystrophic heart disease  

Y Lai and D Duan

Gene Ther 19: 678-685; advance online publication, February 9, 2012; doi:10.1038/gt.2012.10

Abstract | Full Text | PDF

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade  

J Reinkober, H Tscheschner, S T Pleger, P Most, H A Katus, W J Koch and P W J Raake

Gene Ther 19: 686-693; advance online publication, February 16, 2012; doi:10.1038/gt.2012.9

Abstract | Full Text | PDF

Directed evolution of novel adeno-associated viruses for therapeutic gene delivery  

M A Bartel, J R Weinstein and D V Schaffer

Gene Ther 19: 694-700; advance online publication, March 8, 2012; doi:10.1038/gt.2012.20

Abstract | Full Text | PDF


Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Public release date: 30-Jul-2013

Contact: Lauren Woods
The Mount Sinai Hospital / Mount Sinai School of Medicine

Inhalable gene therapy may help pulmonary arterial hypertension patients

Gene therapy when inhaled may restore function of a crucial enzyme in the lungs to reverse deadly PAH

The deadly condition known as pulmonary arterial hypertension (PAH), which afflicts up to 150,000 Americans each year, may be reversible by using an inhalable gene therapy, report an international team of researchers led by investigators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

In their new study, reported in the July 30 issue of the journal Circulation, scientists demonstrated that gene therapy administered through a nebulizer-like inhalation device can completely reverse PAH in rat models of the disease. In the lab, researchers also showed in pulmonary artery PAH patient tissue samples reduced expression of the SERCA2a, an enzyme critical for proper pumping of calcium in calcium compartments within the cells. SERCA2a gene therapy could be sought as a promising therapeutic intervention in PAH.

“The gene therapy could be delivered very easily to patients through simple inhalation — just like the way nebulizers work to treat asthma,” says study co-senior investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine and Professor of Gene & Cell at Icahn School of Medicine at Mount Sinai. “We are excited about testing this therapy in PAH patients who are in critical need of intervention.”

This same SERCA2a dysfunction also occurs in heart failure. This new study utilizes the same gene therapy currently being tested in patients to reverse congestive heart failure in a large phase III clinical trial in the United States and Europe.

“What we have shown is that gene therapy restores function of this crucial enzyme in diseased lungs,” says Dr. Hajjar. “We are delighted with these new findings because it suggests that a gene therapy that is already showing great benefit in congestive heart failure patients may be able to help PAH patients who currently have no good treatment options — and are in critical need of a life sustaining therapy.”

When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. According to researchers, the delivery of the SERCA2a gene produces SERCA2a enzymes, which helps both heart and lung cells restore their proper use of calcium.

“We are now on a path toward PAH patient clinical trials in the near future,” says Dr. Hajjar, who developed the gene therapy approach. Studies in large animal models are now underway. SERCA2a gene therapy has already been approved by the National Institutes of Health for human study.

A Simple Inhalation Corrects Deadly Dysfunction

PAH most commonly results from heart failure in the left side of the heart or from a pulmonary embolism, when clots in the legs travel to the lungs and cause blockages. When the lung is damaged from these conditions, the tissue starts to quickly produce new and enlarged cells, which narrows pulmonary arteries. This increases the pressure inside them. The high pressure in these arteries resists the heart’s effort to pump through them and the blood flow between the heart and lungs is reduced. The right side of the heart then must overcome the resistance and work harder to push the blood through the pulmonary arteries into the lungs. Over time, the right ventricle becomes thickened and enlarged and heart failure develops.

The gene therapy that Dr. Hajjar developed uses a modified adeno-associated viral-vector that is derived from a parvovirus. It works by introducing a healthy SERCA2a gene into cells, but this gene does not incorporate into a patient’s chromosome, according to the study’s lead author, Lahouaria Hadri, PhD, an Instructor of Medicine in Cardiology at Icahn School of Medicine at Mount Sinai.

“The clinical trials in congestive heart failure have shown already that the gene therapy is very safe,” says Dr. Hadri. Between 40-50 percent of individuals have antecedent antibodies to the adeno-associated vectors, so potential patients need to be screened before gene therapy to make sure they are eligible to receive the vectors. In patients without antibodies, the restorative enzyme gene therapy does not cause an immune response, according to Dr. Hadri.

The clinical application of the gene therapy for patients with PAH will most likely differ from those with heart failure. The replacement gene needs to be injected through the coronary arteries of heart failure patients using catheters, while in PAH patients, the gene will need to be administered through inhalation.

This study was supported by National Institutes of Health grants (K01HL103176, K08111207, R01 HL078691, HL057263, HL071763, HL080498, HL083156, and R01 HL105301).

Other study co-authors include Razmig G. Kratlian, MD, Ludovic Benard, PhD, Kiyotake Ishikawa, MD, Jaume Aguero, MD, Dennis Ladage, MD, Irene C.Turnbull, MD, Erik Kohlbrenner, BA, Lifan Liang, MD, Jean-Sébastien Hulot, MD, PhD, and Yoshiaki Kawase, MD, from Icahn School of Medicine at Mount Sinai; Bradley A. Maron, MD and the study’s co-senior author Jane A. Leopold, MD, from Brigham and Women’s Hospital and Harvard Medical School in Boston, MA; Christophe Guignabert, PhD, from Hôpital Antoine-Béclère, Clamart, France; Peter Dorfmüller, MD, PhD, and Marc Humbert, MD, PhD, both of the Hôpital Antoine-Béclère and INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; Borja Ibanez, MD, from Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain; and Krisztina Zsebo, PhD, of Celladon Corporation, San Diego, CA.

  • Dr. Hajjar and co-author Dr. Zsebo, have ownership interest in Celladon Corporation, which is developing AAV1.SERCA2a for the treatment of heart failure. Also,
  • Dr. Hajjar and co-authors Dr. Kawase and Dr. Ladage hold intellectual property around SERCA2a gene transfer as a treatment modality for PAH. In addition,
  • co-author Dr. Maron receives funding from Gilead Sciences, Inc. to study experimental pulmonary hypertension.
  • Other study co-authors have no financial interests to declare.

Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension

  1. Lahouaria Hadri, PhD;
  2. Razmig G. Kratlian, MD;
  3. Ludovic Benard, PhD;
  4. Bradley A. Maron, MD;
  5. Peter Dorfmüller, MD, PhD;
  6. Dennis Ladage, MD;
  7. Christophe Guignabert, PhD;
  8. Kiyotake Ishikawa, MD;
  9. Jaume Aguero, MD;
  10. Borja Ibanez, MD;
  11. Irene C. Turnbull, MD;
  12. Erik Kohlbrenner, BA;
  13. Lifan Liang, MD;
  14. Krisztina Zsebo, PhD;
  15. Marc Humbert, MD, PhD;
  16. Jean-Sébastien Hulot, MD, PhD;
  17. Yoshiaki Kawase, MD;
  18. Roger J. Hajjar, MD*;
  19. Jane A. Leopold, MD*

+Author Affiliations

  1. From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.H., R.G.K., L.B., D.L., K.I., J.A., I.C.T., E.K., L.L., J.-S.H., Y.K., R.J.H.); Cardiovascular Medicine Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (B.A.M., J.A.L.); Hôpital Antoine-Béclère, Clamart, France (P.D., C.G., M.H.); INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France (P.D., M.H.); Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain (B.I.); and Celladon Corporation, San Diego, CA (K.Z.).
  1. Correspondence to Lahouaria Hadri, PhD, Cardiovascular Research Center, Box 1030, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York, NY 10029. E-mail lahouaria.hadri@mssm.edu


Background—Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.

Methods and Results—SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline.

Conclusions—Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.

Key Words:

  • Received January 24, 2013.
  • Accepted June 13, 2013.


Circulation.2013; 128: 512-523 Published online before print June 26, 2013,doi: 10.1161/​CIRCULATIONAHA.113.001585

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

Etiology of Heart Failure

  • Alcoholic
  • Hypertensive
  • Idiopathic
  • Inflammatory
  • Ischemic
  • Pregnancy-related
  • Toxic
  • Valvular Heart DIsease

Administration of Cardiac Gene Therapy for Heart Failure: via Percutaneous Intra-coronary Artery Infusion

  • Gene delivery to viable myocardium

dominance and coronary artery anatomy from angiography determines infusion scenario

  • Antegrade epicardial coronary artery infusion over 10 minutes

60 mL divided into 1,2,3 infusions depending on anatomy

Delivered via commercially available angiographic injection system & guide or diagnostic catheters

Dr. Roger J. Hajjar of the Mount Sinai School of Medicine will present at the ASGCT 15th Annual Meeting during a Scientific Symposium entitled: Cell and Gene Therapy in Cardiovascular Disease on Wednesday, May 16, 2012 at 8:00 am. Below is a brief preview of his presentation.

Roger J. Hajjar, MD

Mount Sinai School of Medicine

New York, NY

Novel Developments in Gene Therapy for Cardiovascular Diseases

Chronic heart failure is a leading cause of hospitalization affecting nearly 6 million people in the U.S. with 670,000 new cases diagnosed every year. Heart failure leads to about 280,000 deaths annually.

Congestive heart failure remains a progressive disease with a desperate need for innovative therapies to reverse the course of ventricular dysfunction. The most common symptoms of heart failure are shortness of breath, feeling tired and swelling in the ankles, feet, legs and sometimes the abdomen. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies.

One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which controls Ca2+ handling in cardiac myocytes on a beat to beat basis. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a).

Over the last ten years we have undertaken a program of targeting important calcium cycling proteins in experimental models of heart by somatic gene transfer. This has led to the completion of a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated vector (AAV) type 1 carrying SERCA2a. In this Phase I trial, there was evidence of clinically meaningful improvements in functional status and/or cardiac function which were observed in the majority of patients at various time points. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation and recent completion of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients. In the phase 2 trial, gene transfer of SERCA2a was found to be safe and associated with benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure.

The 12 month data presented showed that heart failure, which is a progressive disease, became stabilized in high dose AAV1.SERCA2a-treated patients: heart failure symptoms, exercise tolerance, serum biomarkers and cardiac function essentially improved or remained the same while these parameters deteriorated substantially in patients treated with placebo and concurrent optimal drug and device therapy. More recently, the 2-year CUPID data from long-term follow-up demonstrate a durable benefit in preventing major cardiovascular events.

The recent successful and safe completion of the CUPID trial along with the start of more recent phase 1 trials usher a new era for gene therapy for the treatment of heart failure. Furthermore, novel AAV derivatives with high cardiotropism and resistant to neutralizing antibodies are being developed to target a large number of cardiovascular diseases.


Power Point Presentation on Cardiac Gene Therapy –



Gene Therapy for Heart Failure

  1. Lisa Tilemann,
  2. Kiyotake Ishikawa,
  3. Thomas Weber,
  4. Roger J. Hajjar

+Author Affiliations

  1. From the Cardiovascular Research Center, Mount Sinai Medical Center, New York, NY.
  1. Correspondence to Roger J. Hajjar, MD, Mount Sinai Medical Center, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail roger.hajjar@mssm.edu


Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today’s science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.

Circulation Research.2012; 110: 777-793 doi: 10.1161/​CIRCRESAHA.111.252981

Key Words:

  • Received December 8, 2011.
  • Revision received January 29, 2012.
  • Accepted January 30, 2012.


With a better understanding of the molecular mechanisms associated with heart failure and improved vectors with cardiotropic properties, gene therapy can now be considered as a viable adjunctive treatment to mechanical and pharmacological therapies for heart failure. In the coming years, more targets will emerge that are amenable to genetic manipulations, along with more advanced vector systems, which will undoubtedly lead to safer and more effective clinical trials in gene therapy for heart failure.


Figure 1.

AAV entry. 1 indicates receptor binding and endocytosis; 2, escape into cytoplasm; 3, nuclear import; 4, capsid disassembly; 5, double-strand synthesis; and 6, transcription.


Figure 2.

Generation of mutant AAV library and directed evolution to identify cardiotropic AAVs. A, Creation of a library of AAVs through DNA shuffling.B, Selection of cardiotropic AAVs through directed evolution.


Figure 3.

Antegrade coronary artery infusion. A, Coronary artery infusion. The vector is injected through a catheter without interruption of the coronary flow. B, Coronary artery infusion with occlusion of a coronary artery: The vector is injected through the lumen of an inflated angioplasty catheter. C, Coronary artery infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected through an inflated angioplasty catheter and resides in the coronary circulation until both balloons are deflated.


Figure 4.

V-Focus system and retrograde coronary venous infusion. A, Recirculating antegrade coronary artery infusion: The vector is injected into a coronary artery, collected from the coronary sinus and after oxygenation readministered into the coronary artery. B, Retrograde coronary venous infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected into a coronary vein and resides in the coronary circulation until both balloons are deflated.


Figure 5.

Direct myocardial injection and pericardial injection. A, Percutaneous myocardial injection: The vector is injected with an injection catheter via an endocardial approach.B, Surgical myocardial injection: The vector is injected via an epicardial approach. C, Percutaneous pericardial injection: The vector is injected via a substernal approach.


Figure 6.

Excitation-contraction coupling in cardiac myocytes provides multiple targets for gene therapy.



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