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Patient was diagnosed with heart disease and pulmonary hypertension in January 2016 and had a triple-bypass operation at age 69. Interview was conducted six months post-surgery.
Author: Gail S. Thornton, M.A.
Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures
Evergreen, Colorado, an idyllic, peaceful community with an elevation of 8,000 feet west of Denver, offers its residents and visitors a beautiful place for arts and culture, summer and winter sporting activities, and scenic beauty. In fact, Ralph Nichols has lived in the town for more than 20 years.
“This past September [2015] was, particularly, challenging for me, where winter begins quite early for us. It became increasingly painful and difficult to breathe in the freezing temperatures. It seemed that my lungs were inflamed and I couldn’t even stand the cold weather. I thought it might be the beginning of a bad cold, and I wasn’t overly concerned that there was anything terribly wrong.”
At that time, Ralph went to his family physician who performed the usual routine examination with no significant results.
“Many years ago, I developed a mild case of scleroderma, a chronic connective tissue disease. I thought that perhaps my symptoms were the result of some type of inflammation in my body that could be managed with prescription medications.”
Scleroderma is known as an autoimmune disease, which adds an inappropriate amount of collagen to various parts of the body, such as the joints, skin, and later stages, various organs, such as the lungs, in Ralph’s case. Scleroderma can cause the organs to shut down and, eventually, cause death.
“I never let this condition stop me from doing anything as it is life-long condition. It was always something I had to tolerate and work through.”
Image SOURCE: Photographs courtesy of Ralph Nichols and Gabriela Contreras. Top left: Ralph today. Top right: Ralph recovering one month after surgery. Bottom left and center: Ralph with his medical team. Bottom right: Ralph in rehabilitation center.
Over the brutal Colorado winter, Ralph’s symptoms were getting worse. He had no idea that his life would dramatically change over the next few months. He went to see his family physician again. During this physical examination, Ralph was referred to pulmonary and cardiovascular specialists for a routine electrocardiogram, echocardiogram and stress test in order to further diagnose his symptoms. He had always been relatively healthy and fit and never been seriously ill or hospitalized.
“On the outside, Ralph was the picture of good health,” said his wife, Gabriela. “On the inside, his body was telling him that something was wrong.”
Three months later in December 2015, Ralph met with Dr. Alexandra Smart, a pulmonologist, who ordered a chest x-ray and other diagnostic tests, including a right heart catheterization. At that point, Ralph’s medical team grew. It was then determined that Ralph needed to see other cardiovascular specialists and undergo more tests. In January 2016, he met with Dr. Sameer Mehta, cardiologist at Cardiac & Thoracic Surgery Associates, in Lakewood, Colorado, who reviewed his tests to date, listened to Ralph’s symptoms, and told him he needed both a right and left heart cardiac catheterization.
“They gave me sedation for the catheterization procedure and went through my neck with a camera to see what was going on with my lungs and heart. We were all singing together on the way to the operating room. During the procedure, my cardiologist found more than he had anticipated.”
The result was not good. Ralph had major blockages in two main arteries that supply blood to his heart muscle compounded by the fact that his lungs were affected by scleroderma.
“The catheterization was alarming. It showed that my arteries were in bad shape. They were both clogged with atherosclerotic plaque; one of them was 99 percent blocked and the other was 85 percent blocked.”
His cardiologist believed that the blockages would not respond to medications quickly or a stent.
“Even though my father had major heart disease and died two years later of cancer at the age of 56, I thought that I would be immune to this particular experience. After all, I was in good health, exercised regularly, lived a reasonable lifestyle and had a great diet.”
Preparing for Life-Saving and Life-Changing Surgery
Unfortunately, surgery was the next step. Ralph was referred to Dr. Mehta’s colleague, Dr. Patrick D. Rudersdorf, cardiothoracic surgeon at Cardiac & Thoracic Surgery Associates.
“I didn’t leave the hospital that day as expected. Instead, I got a visit from Dr. Rudersdorf and couldn’t believe what he was telling me. My only chance to live was having triple bypass surgery which needed to be done immediately. The doctor met with me that same day to explain the procedure, answer my questions and talk through the details of the rehabilitation period after the surgery.”
Dr. Rudersdorf reassured Ralph that he was doing the right thing and calmed my fears.
“He said that I needed this life-saving surgery because I was at high risk for having a major heart attack. I was shocked, at first, at the thought of the intensity of surgery on my body. It’s a situation that no one likes to be in, but I had to make a decision about alleviating the ongoing pain and pressure in my chest along with shortness of breath due to diseased heart arteries. Coronary bypass surgery was my answer to feeling better — and it essentially gave me my life back.”
Dr. Rudersdorf moved his previously planned morning surgery to another day to accommodate me first thing in the morning. Ralph underwent triple bypass surgery at St. Anthony Hospital in Lakewood, Colorado. The procedure was complex and took eight hours. He was in the hospital for a total of 31 days.
“It was an ordeal that I thought I’d never have to experience. I had no time to call anyone, or time to even contemplate life and death…or even being scared. My wife Gabriela spent the entire time in the hospital, supported by our dearest friends, Norma Delaney and Garret Annofsky, in addition to keeping family and friends in other parts of the United States and Mexico updated as well. Once the surgery was over, the medical team woke me up and said the procedure was successful, but I was far from being out of the woods.”
Ralph had some complications because of a condition called pulmonary hypertension, a type of high blood pressure that affects the arteries in the lungs and the right side of the heart. According to the Mayo Clinic’s web site, in one form of pulmonary hypertension, tiny arteries in the lungs, called pulmonary arterioles, and capillaries become narrowed, blocked or destroyed. This makes it harder for blood to flow through the lungs, and raises pressure within the lungs’ arteries. As the pressure builds, the heart’s lower right chamber (right ventricle) must work harder to pump blood through the lungs, eventually causing the heart muscle to weaken and fail. http://www.mayoclinic.org/diseases-conditions/pulmonary-hypertension/home/ovc-20197480
“The pulmonary hypertension limited some of the medications that the doctors would have used during my recovery. It was a tough few days for me in intensive care, hooked up to about 18 monitors. The medical team had to stop and re-start my heart four different times because of atrial fibrillation — finally getting both parts of the heart to dance together in the same rhythm.”
Ralph’s heart was beating abnormally fast and irregular and not functioning the way it should. The doctors restore regular rhythm to the heart by sending an electrical shock to the heart, which is called electrical cardioversion or chemically using antiarrhythmia medications, which is called pharmacologic or chemical cardioversion.
“The doctors shocked my heart first chemically with medications when I was awake. This procedure was the scariest. I was sitting up in bed and felt my heart stop, then the medical team flushed the medication out with saline in order to restart my heart. That procedure was not successful, so that is why the doctors had to shock my heart three more times electrically.
“The reason the doctors stopped my heart was to correct the atrial fibrillation and to get my heart into regular sinus rhythm, which is a wave mode of the heart where everything is synchronized. The doctors did not want me to continue to experience atrial fibrillation because if continued, I would not be able to regain my strength.”
Ralph was finally moved from intensive care to intermediate care after five days and the medical team kept him in intermediate care another 12 days until his heart and lungs got stronger.
“From there, I didn’t go home but instead went to Evergreen Life Center for rehabilitation for two weeks to learn how to walk, climb stairs so that I could access my home on my own, and develop my strength again. The rehab team would let me leave only after making sure I had oxygen in my home.”
After that, Ralph started another phase of his rehabilitation at St. Anthony Cardiac Rehabilitation and Wellness Center. For the next three months, he took part in cardiac rehabilitation three days a week. He passed that with flying colors. Now, he is in another phase of rehabilitation, building his lung capacity two days a week.
Ralph didn’t have the means or even the will to communicate with friends during this tumultuous time, except Gabriela and several close friends who were always at the hospital and rehabilitation center who gave him the strength to continue.
“I finally returned home after many weeks with an enormous feeling of gratitude for each and every one of my friends, as well as the St. Anthony’s hospital team of doctors, nurses, and therapists, who supported me and Gabriela during this exceptional adventure that has certainly changed my life.”
Surely, this experience has been a life-changing experience for Ralph.
Coronary Artery Bypass Facts
Coronary artery bypass grafting (CABG, often pronounced “cabbage”) is a surgical treatment for blocked coronary arteries. Coronary arteries supply blood to the heart muscle and when blockages in these arteries form, chest pain, shortness of breath and heart attacks can occur. Catheter procedures performed by interventional cardiologists address the blockages themselves with stents. Coronary bypass surgery performed by cardiac surgeons reroutes the blood around the blockages to supply better blood supply to the heart muscle and is a better treatment option, although more invasive, for certain patients and more durable for most patients.
Today, Ralph is regaining his strength both in mind and body. He visits the cardiovascular and pulmonary rehabilitation center three times a week for the past few months and walks on their treadmill, lifts weights and pedals the bicycle for one hour, supervised by the therapists. He also sees his medical team for regular check-ups every month, eats healthier with no fat and no salt, and takes a cocktail of medicines daily for his heart and lungs, including amiodarone, furosemide, pitavastatin, and aspirin.
“Almost six months after my surgery, although I am not in the best shape of my life, however, I am in the best spiritual place than ever before. This is a huge milestone for me. I continue to improve my strength, which will make my heart more resilient. There is nothing that I can’t do now, and I am doing everything I can to experience a normal life as far as work and regaining my strength. I find it necessary to move to a warmer climate and lower altitude in order to continue to improve.”
Ralph also is the former lead singer of The Letterman and The Sandpipers, two American easy-listening bands during the 1960-70-80s. He is an entertainer at heart with over 3,000 professional appearances to his credit. He has been performing and recording for over 50 years, traveled the world extensively and performed before members of the Vatican with Pope Pius XII and Royalty with Prince Rainier and Princess Grace Kelly, as well as notables such as Frank and Nancy Sinatra, Tony Bennett, Ronald Reagan, Merv Griffin, Danny Thomas, Shirley Bassey, Rosalind Russell and Bob Hope.
Ralph and his vocal group were dubbed by Billboard Magazine as “the greatest romantic vocal group of all time.” He is also a member of the Vocal Group Hall of Fame, a prestigious honor. He is a true legend as his group has sold more than 20 million recordings, performed live thousands of times, and whose recording of the song “Love” was left by NASA astronauts in a time capsule on the moon.
“I enjoy each and every day and appreciate all that life has to offer.”
Ralph’s next step is to get back to singing and his solo entertainment business, which he holds dear to his heart. That should be a task that he can easily accomplish.
Editor’s note:
We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support that she provided in scheduling time to talk with Ralph Nichols.
Ralph Nichols provided his permission to publish this interview on July 30, 2016.
No evidence to change current transfusion practices for adults undergoing complex cardiac surgery: RECESS evaluated 1,098 cardiac surgery patients received red blood cell units stored for short or long periods
I wish to encourage the e-Reader of this Interview to consider reading and comparing the experiences of other Open Heart Surgery Patients, voicing their private-life episodes in the ER that are included in this volume.
I also wish to encourage the e-Reader to consider, if interested, reviewing additional e-Books on Cardiovascular Diseases from the same Publisher, Leaders in Pharmaceutical Business Intelligence (LPBI) Group, on Amazon.com.
Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013
Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015
Don’t Ignore the Many Lessons of the MitraClip Failure
John M. Mandrola, MD
August 30, 2018
Comments
It would be wrong to say that use of this device for this indication provided no benefit to patients. The more accurate conclusion is that the MitraClip caused net harm. That’s because in addition to no benefit in the efficacy endpoints, patients in the device group endured a procedural complication rate of more than 10%, including a sevenfold higher rate of stroke.
Once again, we can learn both specific lessons about the treatment of people with heart failure and more general lessons on the acceptance of untested therapeutics.
Other comments
Dr. MIGUEL QUINTANA| Cardiology, General
A bad day for interventional cardiology. I do believe that interventional cardiologist are aware about the mechanisms of severe MR in dilated hearts, however when a point of no return in those ventricles is reached, something has to be done.
I do agree with Dr. Mandrola regarding the behaviour of the industry to drive new devices in medical practice without performing RCT. However the main responsible are the institutions approving the devices (FDA and European Commission for drugs and devices).
I wish to hear some comments of Dr. Mandrola regarding the new trends in performing RCT using just the non-inferiority criteria and the growing trends of using the “big data” of mega data registries to establish guidelines for clinical treatments and not only to test new hypothesis.
Dr. James Rittelmeyer| Cardiology, Interventional
When the point of no return has been reached palliative care is a great plan. It causes no harm and is relatively inexpensive.
Dr. Johannes Schaar| Cardiology, General
Right!!!!!! We should stay away from interventional cardiologists, who have know idea what they do and are on the payroll of the industry
This link suggests that the only FDA approved device may have a more limited indication, but is still helping the very sickest patients, with the ‘negative’ outcome for the quoted study. Functional Mitral Regurgitation (6 M patients in the US) still has no approved viable transcatheter therapy, and the interpretations of the latest study results suggest a more restricted patient selection for the MitraClip®device.
Edward Hlozek, Chairman and CEO, ValveCure, LLC, on 8/30/2018
BarrelEye portends to be available to all classes of patients with Functional MR and significantly improve quality of life and extend lives, offering future non-invasive repeatability of the therapy, without an implant.
Earlier Intervention for Mitral Valve Disease May Lead to Improved Outcomes
Slow progression of disease may mask symptoms until damage cannot be fully repaired
In this study, the data showed that the overall repair rate was 65.6 percent (57,244) and the replacement rate was 34.4 percent (29,970). Overall operative mortality was 2 percent (1,762).
“We found that the number of operations performed for mitral valve disease is growing faster than any other category of heart operation and that the results were excellent with low risks of death and complications,” said Gammie.
The researchers also revealed that while the prevalence of mitral valve disease and the number of mitral valve operations performed per year are increasing, overall aortic valve operations were performed 1.6 times more commonly than mitral valve operations during the study period.
“This may suggest important under-referral and under-treatment of mitral valve disease, which may be related to the slower progression of signs and symptoms of mitral compared to aortic disease, as well as potential lack of adherence to guidelines for intervention,” said Gammie. “So although contemporary outcomes are excellent, there remains an important and substantial opportunity to improve results for patients with mitral valve disease by following established guidelines and encouraging earlier referral for operation.”
Percutaneous repair or replacement for mitral regurgitation?
by Ted E. Feldman, MD
by Nicole Lou
Contributing Writer, MedPage TodayApril 04, 2017
Mitral repair is still a relatively youthful field at 14 years, but now operators are taking it further and developing methods for mitral valve replacement, says Ted E. Feldman, MD, of Evanston Hospital in Illinois, where mitral repair first got its start.
In this exclusive MedPage Today video, the interventionist shares his insight into the limitations of the device synonymous with mitral repair, the MitraClip, and discusses the current challenges of outright percutaneous replacement of the valve.
“100 patients underwent Mitral valve repair vs 1000s of Aortic valve the TAVR.”
MV repair via transcatheter valve implant (TMVR) will be extremely difficult to get right because of the complex nature of the anatomy versus the simple circle that is the aortic valve (TAVR)…and MitraClip is limited because leaflets sometime cannot be caught right for the device to be implanted. Think of ValveCure’s platform device that is not an implant and tightens up the valve biologically.
Aortic and Pulmonic are basically planar circular shapes. The shape of the Mitral and Tricuspid are parabolic ellipsoidal. This unique shape makes designing a transcatheter mitral valve implant challenging, especially considering that most are of a unique shape and dimension. And the aortic is more calcified, which lends to a better attachment of a transcatheter implant because it is more rigid and planar.
MitraClip Issues, Outcomes Come to Fore in US Registry Experience
by Nicole Lou
Reporter, MedPage Today/CRTonline.org
10.03.2016
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Cardioband is a product of Valtech acquired by Heartware in 2015. Medtronic completed acquisition of Heartware in August 2016. See Updates, below
A novel surgical-style transcatheter device showed promise for the treatment of functional mitral regurgitation, investigators reported.
The Cardioband direct annuloplasty device was associated with no periprocedural deaths and had a 1-month mortality rate of 5%, according to Georg Nickenig, MD, of Heart Center Bonn in Germany, and colleagues in their study published online in JACC: Cardiovascular Interventions. By 6 months, the death rate had climbed to 9.6%.
Annular septolateral dimensions fell from 3.7 cm at baseline to 2.5 cm at 1 month and 2.4 cm after 6 months (P<0.001) with the device, which is implanted in a transvenous, transseptal procedure to encircle the valve annulus and, secured with small anchors, cinch it until the valve closes fully again.
In addition, the proportion of patients with grade 3 or worse mitral regurgitation also dropped from 77.4% to 10.7% at 1 month (P<0.001) and was recorded at 13.6% after 6 months (P<0.001). The proportion still categorized as being in New York Heart Association functional class III or IV dropped from 95.5% at baseline to 18.2% (P<0.001).
Over the 6-month follow-up in the study, exercise capacity generally improved (332 m in a 6-minute walking test versus 250 m at baseline, P<0.001), as did patients’ quality of life (Minnesota Living With Heart Failure Questionnaire score 18.1 versus 38.2 at baseline,P<0.001).
Medtronic Completes Acquisition of HeartWare International
Broadens Heart Failure Leadership Into Growing Circulatory Support Sector
DUBLIN – Aug. 23, 2016 – Medtronic plc (NYSE: MDT), the global leader in medical technology, has completed its acquisition of HeartWare International, Inc., a leading innovator of less-invasive, miniaturized, mechanical circulatory support technologies (MCS) for treating patients with advanced heart failure. HeartWare will become part of the Heart Failure business within the Medtronic Cardiac Rhythm and Heart Failure division. Under the terms of the transaction, each outstanding share of HeartWare common stock has been converted into the right to receive $58.00 in cash, without interest, subject to any required withholding of taxes.
HeartWare develops and manufactures miniaturized implantable heart pumps, or ventricular assist devices (VAD), to treat patients around the world suffering from advanced heart failure. Its flagship product, the HVAD® System, features the world’s smallest full-support VAD and is indicated for refractory end-stage left-ventricular heart failure patients in the U.S. who are awaiting a heart transplant, as well as approved in Europe for long-term use in patients at risk of death from refractory, end-stage heart failure.
Medtronic estimates that the global VAD market is approximately $800 million currently, and worldwide is expected to grow in the mid-to-high single digits for calendar years 2016-17, and accelerate to high-single/low-double digits beyond calendar year 2017.
“Not only does the current HeartWare portfolio expand Medtronic leadership across the heart failure continuum, its product pipeline – when married with our expertise – can result in progressively less-invasive heart pumps that have the potential to benefit even more patients,” said David Steinhaus, M.D., vice president and general manager of the Heart Failure business, and medical director for the Cardiac Rhythm and Heart Failure division at Medtronic. “Today, Medtronic offers the industry’s leading cardiac resynchronization therapy devices, including MR-conditional CRT-defibrillators; MCS therapy for advanced heart failure patients; heart failure diagnostics; and meaningful expert analysis through Medtronic Care Management Services, including the recently launched Beacon Heart Failure Management Service.”
The acquisition of HeartWare broadens the Medtronic portfolio of therapies, diagnostic tools and services for patients suffering from heart failure, aligning with Medtronic’s Mission of alleviating pain, restoring health and extending life. The acquisition is part of the Company’s therapy innovation strategy to surround the physician with innovative products while focusing on patients and disease states.
“This is an exciting moment, as more than 600 HeartWare employees are now part of the broader Medtronic organization,” said Doug Godshall, who served as president and chief executive of HeartWare for the past decade. “HeartWare has delivered incredible advancements for patients suffering from heart failure, through the commercialization of the HVAD system and pipeline development, and I am convinced that being part of Medtronic will allow us to accelerate meaningful innovations even more quickly.”
Heart failure, also known as congestive heart failure, is a condition in which the heart isn’t pumping enough blood to meet the body’s needs. Heart failure usually develops slowly after an injury to the heart. Some injuries may include a progressive deterioration of the heart muscle, heart attack, untreated high blood pressure, or heart valve disease. Heart failure remains a leading cause of hospitalization and death in the United States, and its prevalence continues to increase, affecting more than 5 million people in the U.S. alone. The cost of heart failure is high. Healthcare expenditures in the U.S. on heart failure are estimated to be approximately $39 billion per year, making it one of the largest expenses to the healthcare system. With the aging of the population, Medtronic estimates that the number of patients with heart failure could exceed 8 million by 2030.
This transaction is expected to meet Medtronic’s long-term financial metrics for acquisitions. Medtronic does not intend to modify its fiscal year 2017 revenue outlook or earnings per share (EPS) guidance as a result of this transaction, although it is expected to provide increased confidence in the company’s ability to deliver on its FY17 revenue growth outlook. In addition, Medtronic expects minimal to no net EPS dilution from this transaction for the first two years as the company intends to offset the expected dilutive impact. The acquisition is expected to be earnings accretive in year three.
In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services of the highest quality that deliver clinical and economic value to healthcare consumers and providers around the world.
The Tender Offer and Merger The tender offer for all of the outstanding shares of HeartWare common stock expired as scheduled immediately after 11:59 p.m. Eastern time on August 22, 2016. Computershare Trust Company, N.A., the depositary and paying agent for the tender offer, has advised Medtronic that 14,952,817 shares of HeartWare common stock were validly tendered and not properly withdrawn in the tender offer, representing approximately 85.15% of the outstanding shares. All of the conditions to the tender offer have been satisfied, and on August 23, 2016, Medtronic Acquisition Corp., a subsidiary of Medtronic, accepted for payment and will promptly pay for all shares validly tendered and not properly withdrawn in the tender offer.
Following acceptance of the tendered shares, Medtronic completed its acquisition of HeartWare through the merger of Medtronic Acquisition Corp. with and into HeartWare without a vote of HeartWare’s stockholders pursuant to Section 251(h) of the Delaware General Corporation Law. As a result of the merger, HeartWare became a wholly-owned subsidiary of Medtronic. In connection with the merger, all HeartWare shares not validly tendered into the tender offer (other than shares (i) owned by HeartWare as treasury stock or owned by Medtronic, Inc. or Medtronic Acquisition Corp., which shares were cancelled and retired and cease to exist or (ii) held by any person who was entitled to and has properly demanded statutory appraisal of his or her shares) have been cancelled and converted into the right to receive the same $58.00 per share in cash, without interest, subject to any required withholding of taxes, as will be paid for all shares that were validly tendered and not properly withdrawn in the tender offer. HeartWare common stock will cease to be traded on The NASDAQ Stock Market LLC.
About Medtronic Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world’s largest medical technology, services and solutions companies – alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 85,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together.
Two-year outcomes from the National Institutes of Health (NIH)–sponsored Cardiac Surgery Clinical Research Network (CTSN) trial suggest that patients with severe ischemic mitral regurgitation (MR) fare just as well when the valve is repaired or replaced, at least when it comes to measures of left ventricular reverse remodeling and survival, but that replacing the mitral valve provides a more durable correction of MR[1].
Presenting the results of the CTSN trial here at the American Heart Association (AHA) 2015 Scientific Sessions, the researchers reported no significant difference in the mean left ventricular end-systolic volume index (LVESVI) among 251 patients randomized to mitral-valve repair or chordal-sparing mitral-valve replacement.
In addition, there was no mortality advantage with either approach. The 2-year mortality rate was 19.0% in the repair arm and 23.2% in the replacement group, a difference that was not statistically significant (hazard ratio 0.79; 95% CI 0.46–1.35).
Despite the equivocal results, investigators, including lead researcher Dr Daniel Goldstein (Montefiore Medical Center/Albert Einstein College of Medicine, New York), did observe significantly higher recurrence rates among patients who underwent surgical repair. At 2 years, 59% of patients in the repair arm and 3.8% in the replacement arm were diagnosed with moderate or severe MR (P<0.001).
“Recurrence was rather striking,” said Goldstein during a press conference announcing the results. “Interestingly, most of the recurrences were moderate, were not severe.”
This difference in MR translated into a significantly increased risk of heart failure at 2 years among patients undergoing mitral-valve repair (24.0% vs 15.2% in the repair and replacement arms, respectively; P=0.05) as well as an increased readmission rate to hospital for cardiovascular causes (48.3% vs 32.2%, respectively;P=0.01).
Dr Daniel Goldstein
“There was no difference in the total readmissions to the hospital between groups,” said Goldstein. “However, if you look at just cardiovascular readmissions, there was a striking difference, with repair patients requiring many more heart-failure readmissions than replacement patients. What were those heart-failure readmissions for? They were for true heart failure or for the placement of an ICD or biventricular pacers, which in essence are also heart-failure readmissions because the people who are getting those technologies are people with advanced heart failure.”
The bottom line, say investigators, is that the 2-year data reveal a divergence in clinical outcomes not evident at 1 year. The deficiency in the durability of correction of MR with surgical repair is “disconcerting,” they add, noting that MR recurrence predisposes patients to heart failure, atrial fibrillation, increased hospitalizations, and other adverse outcomes.
The 2-year results are published November 9, 2015 in the New England Journal of Medicine to coincide with the late-breaking clinical-trials presentation. One-year outcomes presented at the AHA 2013 meeting and reported by heartwirefrom Medscape at that time.
Who Should Get Repair? Who Replacement?
Dr Alain Carpentier (Descartes University, Paris, France), one of the world leaders in mitral-valve repair, said the findings are particularly important for younger, less experienced surgeons. “If these results are confirmed, it means that the young surgeon with little experience in valve repair shouldn’t feel guilty for replacing a valve because he or she will be certain that the result will be as good.”
Valve repair, added Carpentier, is a “question of experience” and should be done only by surgeons with a large amount of clinical practice in the surgical technique. The present study is unique as the surgeons performing the procedure in BEAT-HF were experienced surgeons, a component of the trial that partially explains why repair and replace both fared as well in terms of the primary end point.
Speaking with the media, Goldstein said physicians who support valve repair believe it is associated with lower morbidity and mortality, noting that it results in the preservation of the entire mitral subvalvular apparatus. MR recurrence is a known problem, however, and this can lead to functional mitral stenosis if the ring is very small. Replacement, on the other hand, is associated with higher perioperative morbidity and mortality, but it does provide a more durable correction of MR.
Goldstein said that even though there was no difference in LVESVI at 2 years or in mortality either, recurrence is a factor that will weigh in a decision over whether or not to repair or replace the mitral valve. Right now, he is comfortable performing a mitral-valve replacement as first-line treatment in a majority of patients. “I think we still need to follow these patients a little longer, because you have to remember you have a prosthesis in there,” he said. “The prosthesis can give you problems. There’s thromboembolic complications, it can get infected, it can deteriorate and need rereplacement, so the balance of those issues awaits more time.”
That said, in the absence of reliable predictors of a successful mitral-valve repair, surgical replacement of the mitral valve is a viable option. “Based on experience, I think a lot of people want to start thinking a little more liberally about replacing the valve in general just because of these data,” he said. Optimal valve-replacement candidates would include individuals with a basal aneurysm or basal dyskinesia, he noted.
Goldstein reports grant support from the National Institutes of Health and consulting fees from Medtronic. Disclosures for the coauthors are listed on the journal website.
UPDATED Sept. 10, 2015, with details on MVAD trial pause, expanded field action and Valtech acquisition.
HeartWare International (NSDQ:HTWR) today said it’s pausing enrollment in a clinical trial of its next-generation MVAD heart pump while it looks to fix an issue with the manufacturing process for the left ventricular assist device’s controller.
“There was a feeding frenzy starting to develop around Valtech. We agreed with them that we would put in a 2nd investment earlier this year that would buy us an exclusivity period that expired mid-September. It was quite clear from the communications we were getting from the company that they were having to fend off interest from others. It was also quite clear from the company that they are an R&D powerhouse that doesn’t really want to build a commercial organization,” he said. “Frankly if we couldn’t do Valtech, we weren’t going to do mitral because we believe we need the ability to repair surgically and repair interventionally and we believe we need a portfolio.”
Implications of this M&A on the Global EcoSystem for Carviovascular Repair Tools Segment
September 6, 2015
It is my strong belief that HeartWare inked $929m deal for Valtech Cardio’s mitral and tricuspid valves Is creating a new constellation of concentration among players, thus M&A could be the optimal solution as a fallout from the new reality of $1Billion investment in Israeli Valtech, for many Early stage Start Ups in the Mitral Valve Repair and Replacement Segment.
What implications this deal has on the Mitral Valve Repair Technology Start Ups vs Mitral Valve Replacement OEM of Artificial Valves?
Percutaneous Annuloplasty May Offer Safe, Effective Alternative to Surgery for HF Patients With MR
What are the Market implications of this announcement on
Medtronic
Edwards LifeSciences
St. Jude (new announcement)
Abbot
In addition,
Lev-Ari, A. 6/22/2012Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Lev-Ari, A. 6/19/2012Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market
Lev-Ari, A. 6/22/2012Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders)in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Medtronic (NYSE:MDT) said today that it agreed to pony up as much as $458 million for Twelve Inc. and its transcatheter mitral valve implant, as the race to get a TMVI device to market heats up.
Twelve, a spinout from the Foundry incubator that’s based in Redwood City, Calif., is backed by Domain Associates, Versant Ventures, Morgenthaler Ventures, Longitude Capital, Emergent Medical Partners, Vertex Venture Management, and Capital Group, Fridley, Minn.-based Medtronic said.
The deal calls for a $408 million payment once the deal closes, expected in October, and another $50 million pegged to CE Mark approval in the European Union for the Twelve TMVI device.
“Upon close, this acquisition will strategically augment our existing capabilities in the transcatheter mitral space, which represents an important growth opportunity for Medtronic,” coronary & structural heart president Sean Salmon said in prepared remarks. “We have followed the transcatheter mitral valve space closely and firmly believe that Twelve has the most novel technology along with a strong, proven team. The combined strengths of our organizations will significantly accelerate our ability to deliver an exciting and differentiated therapy to patients, physicians and healthcare systems around the world.”
Edwards Lifesciences (NYSE:EW) last week said it agreed to pay $400 million for CardiAQ Valve Technologies and its transcatheter mitral valve implant, saying it also reached a deal to revise the protocol for restarting a trial of its own Fortis mitral valve.
The deal for CardiAQ Valve, which like Edwards is based in Irvine, Calif., calls for an up-front payment of $350 million in cash and another $50 million pegged to “achievement of a European regulatory milestone,” Edwards said. The deal is expected to be “slightly dilutive” to 2015 earnings, the company said.
“Edwards’ primary strategy is to create valuable therapies that transform patient care. We believe the acquisition and integration of CardiAQ will advance our development of a transformational therapy for patients with mitral valve disease who aren’t well-served today,” chairman & CEO Michael Mussallem said in prepared remarks. “While still early in the development of this therapy, the progress of the team of employees and clinicians working on our Fortis mitral replacement system has reinforced our confidence in a catheter-based approach. We believe the experiences and technologies of Fortis and CardiAQ are complementary and that this combination will enable important advancements for patients.”
“CardiAQ is proud of our pioneering efforts in the early development of this transcatheter mitral valve therapy conceived by cardiac surgeon Dr. Arshad Quadri. We believe our technology, which incorporates multiple delivery approaches with a single valve, shows great promise for patients,” added CardiAQ CEO Rob Michiels.
In April, CardiAQ won an investigational device exemption from the FDA for a 20-patient feasibility trial of its as-yet-unnamed TMVI candidate, with a protocol calling for 10 subjects to be treated transfemorally and another 10 treated via the transapical approach.
“We look forward to joining Edwards, whose experience and leadership as a developer of breakthrough therapies for heart valve disease will advance our work,” co-founder, president & COO Brent Ratz said in a statement.
Edwards also said it reached a deal with the investigators in its Fortis trial for changes to study’s protocol, after blood clots in some of the 20 patients implanted with the device prompted a temporary halt for the trial.
Abbott’s percutaneous MitraClip mitral valve repair device SUPERIOR to Pacemaker or Implantable Cardioverter Defibrillator (ICD) for reduction of Ventricular Tachyarrhythmia (VT) episodes
Harpoon Medical is a development stage medical device company commercializing a minimally invasive, image guided surgical tool for beating heart mitral valve repair. The technology was developed in the Division of Cardiac Surgery at The University of Maryland School of Medicine. With the Harpoon device, surgeons can access and repair the mitral valve in a beating heart via a small incision between the ribs without the need for cardiac arrest or cardiopulmonary bypass. The tool enters the left ventricle transapically and inserts “bulky knot” neochords in the leaflet to eliminate mitral valve regurgitation. When introduced to the market, the Harpoon device should transform the traditional open heart mitral valve surgical procedure from a complex 3-6 hour operation to a 60-minute procedure and reduce the recovery period from weeks to days.
Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation
Michael A. Acker, M.D., Michael K. Parides, Ph.D., Louis P. Perrault, M.D., Alan J. Moskowitz, M.D., Annetine C. Gelijns, Ph.D., Pierre Voisine, M.D., Peter K. Smith, M.D., Judy W. Hung, M.D., Eugene H. Blackstone, M.D., John D. Puskas, M.D., Michael Argenziano, M.D., James S. Gammie, M.D., Michael Mack, M.D., Deborah D. Ascheim, M.D., Emilia Bagiella, Ph.D., Ellen G. Moquete, R.N., T. Bruce Ferguson, M.D., Keith A. Horvath, M.D., Nancy L. Geller, Ph.D., Marissa A. Miller, D.V.M., Y. Joseph Woo, M.D., David A. D’Alessandro, M.D., Gorav Ailawadi, M.D., Francois Dagenais, M.D., Timothy J. Gardner, M.D., Patrick T. O’Gara, M.D., Robert E. Michler, M.D., and Irving L. Kron, M.D. for the CTSN
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.
METHODS
We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.
RESULTS
At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.
CONCLUSIONS
We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes.
(Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.)
Verna Hoy knew something wasn’t right; she was coughing a lot and running out of breath. Both her mother and a sister had heart murmurs — which doctors heard in Hoy’s chest, too — so she wasn’t surprised to be referred to a cardiologist.What cardiologists found would not be so simple to fix, however. At least, it didn’t use to be. Hoy had two problems: a leaky mitral valve in her heart, which caused blood to back up into her left atria, and something called hypertrophic cardiomyopathy (HCM) that obstructed blood flow in her heart. And the only way to fix it, before, was risky and invasive open heart surgery. But doctors didn’t want to do that to the 87-year-old from Richfield.Instead, her cardiologist turned to a just-approved device called a MitraClip that could be deployed via a catheter snaked up to her heart through a vein in her leg.On Dec. 11, Hoy became the first patient in Minnesota to receive the MitraClip to repair a leaky mitral valve. Turns out, Hoy also is the first person in the world to also have her HCM treated with the same device.“They decided they would try this procedure to see if it would work,” Hoy said recently. Its seems to be working just fine. A week after her procedure, Hoy was washing clothes, running errands to the grocery store and drugstore and heading out to lunch.”We’re all very excited about it,” said Dr. Paul ?Sorajja, an interventional cardiologist at the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. “This is a new advance in the management of patients with HCM.”The combination of HCM and a faulty mitral valve affects 400,000 Americans. The MitraClip, developed by Abbott Laboratories, won approval from the Food and Drug Administration in October. It has been available in Europe for several years.
The MitraClip is the only commercially available mitral valve repair device that can be placed into the heart through a blood vessel, a much less-invasive process that speeds patient healing.
Sorajja and Dr. Wes Pedersen, director of the Transcatheter Valve Therapy Program at the Minneapolis Heart Institute, were investigators into the safety and effectiveness of the procedure during clinical trials.
“The device has proved its effectiveness in research studies and we are excited to see this device commercially available and improving and extending the lives of thousands of people,” Sorajja said. “When we looked at how this device can be used to treat mitral regurgitation, we felt that it could also be used to simultaneously treat obstruction due to HCM.”
HCM is a condition in which the walls of the heart thicken, interfering with the heart’s activities. In Hoy’s case, a thick wall in her left ventricle slowed the flow of blood out of the ventricle. At the same time, the thickening caused the mitral valve in her heart to leak blood into her left atrium — called mitral regurgitation. That combination was hurting Hoy.
For patients with HCM, doctors usually open the chest to remove part of the thickened heart wall. In some cases, they inject alcohol into the tissue to kill it, causing a small heart attack. But the MitraClip, which essentially clips the middle of the leaky mitral valve, also keeps that valve from further obstructing blood flow, Sorajja said. One device, two problems solved.
According to the FDA, repairing the valve during open heart surgery still is the preferred method. But MitraClip is now acceptable for patients who are not considered healthy enough for the surgery.
Sorajja, who came to Abbott Northwestern from the Mayo Clinic, said, “We had our suspicions that this would work. It was a great day. It was a really great day for us. We are so happy.”
Hoy, who was discharged from the hospital just two days after the procedure, said she still gets a little breathless.
“I seem to be OK,” she said. “I was told not to lift anything over 10 pounds and I watch it.”
She said trying a new device didn’t worry her. Besides, she likes the idea of maybe helping others with what doctors learn from her.
“There are a lot of people on this Earth,” she said. “If it is my time, so be it. But I thought if it would help other people, I would take a shot.” ___
A. Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
A.1 Patient Segments by Medical Diagnosis
If a patient is disqualified for CABG then the patient is likely to be disqualified for Open Heart Surgery for Mitral Valve Repair and Replacement.
For all cases that a percutaneous Transcatheter for Mitral Valve Repair is deemed to be non indicated – the patient’s SOLE choice is the proposed Non-Ablative Fully Non-Invasive Procedure – a novel technology under development by Dr. Pearlman.
Special Patient Subsets
A. Elderly Patients
Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.
B. Women
A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.
ACC/AHA Practice Guidelines, ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)
Current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated patients.
Before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation.
Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is
severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death.
Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6.
Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1).
Other risk factors for cardiovascular morbidity include
Presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example
Mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
In the U.S. over 5 million patients are estimated to suffer from moderate to severe mitral regurgitation with an additional 300,000+ new patients diagnosed annually. In Western Europe the number is comparable and other medically advanced countries around the world add to this addressable patient population. The rest of the world market has been assumed to be equal to twice the size of the US market.
Of these over 5 million patients in the US, about 130,000 have annuloplasty surgeries every year (about 65% repair and 35% replacement). Another 700,000 are deemed high risk. These high risk patients represent a non-served market because there is no non-implantable device/simpler surgical procedure available.
Due to the surgical probe and lateral device’s inherent simplicity of application compared to current implantable techniques, ValveCure forecasts that in addition to capturing some of the current annuloplasty procedures, a large number of currently unserved mitral regurgitation patients will avail themselves of this new technology.
Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVRe), because MVRe produces superior long-term outcomes. In addition, MVRe can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patients—especially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVRe. Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVRe technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVEREST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVRe. However, MVRe is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development.
“LPBI Proposals for Precision Mitral Annuloplasty: Extensions to RF Solutions and MRI Methods and Devices”
Inventor and Author:Justin D Pearlman, MD, PhD, FACC
The primary goal for therapy of mitral regurgitation is reduction in the leakage without causing stenosis (excessive flow resistance), prior to the development of fibrosis of heart muscle secondary to abnormal workload. The specific treatment can be adapted to the specific mechanism of the valve leakage. Mechanisms of mitral regurgitation include prolapse (leaflet inversion) due to a large excessively flexible leaflet and/or excessive length of chordae, malcoaptation/incomplete valve closure assocated with relatively large or dilated annular support, or rarely, perforation of a leaflet. Shrinkage of excessive tissue can be achieved surgically or non-surgically. Under non-disclosure we can elaborate on proprietary methods that can achieve these goals surgically or non-surgically, either with direct contact (invasive) but without requiring cardiac bypass, robotic catheter (minimally invasive) or with no skin breach at all (completely non-invasive).
C.1 Three extensions of ValveCure Non-Hardware Surgical Mitral Annuloplasty
C.2 Three non-Surgical Alternatives to RF Mitral Annuloplasty: Response Modulated Excitation – MRi Methods and Devices
C.3 Features of Novel Technology: MRI Methods and Devices
Three extensions of Current Non-Hardware Surgical Mitral Annuloplasty
Three Less Invasive methods
For the full presentation go to the link, below and request access for the PASSWORD PROTECTED Article by e-mailing to the inventor
Dr. David H. Adams is the Marie-Josée and Henry R. Kravis Professor and Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center. Dr. Adams is a leader in the field of mitral valve reconstruction and heart valve surgery. As Program Director of Mount Sinai’s Mitral Valve Repair Reference Center, he has set national benchmarks for the specialty with a repair success rate of more than 99 percent in patients with degenerative mitral valve disease, while running one of the largest and most respected valve programs in the United States.
Dr. Adams’ impact extends far beyond his own operating room. As the holder of multiple patents, he carries out a prodigious research agenda to develop new techniques and tools to push frontiers in complex valve surgeries and make procedures safer for patients. He is the co-inventor of two mitral valve annuloplasty repair rings (the Carpentier-Edwards Physio II Annuloplasty Ring and the Carpentier-McCarthy-Adams IMR ETlogix Ring), and inventor of a new tricuspid annuloplasty ring (Medtronic Tri-Ad Tricuspid Annuloplasty Ring) and has royalty agreements with Edwards Lifesciences andMedtronic. Dr. Adams has performed the first successful implantations of the IMR ETlogix, Physio II, and Tri-Ad Rings in the United States. All of these rings are now used extensively throughout the world.
Dr. Adams is a much sought after speaker both nationally and internationally and has given over 300 invited lectures and operated on patients in multiple teaching courses throughout the world. His desire to share knowledge and collaborate with other cardiac surgeons led him to develop one of the world’s largest video libraries of techniques in valve reconstruction. He is the author of over 200 publications, and is recognized as a leading surgeon scientist and medical expert, serving on the Editorial Boards of several medical journals, including Cardiology and The Annals of Thoracic Surgery. He is currently the Co-Editor of Seminars in Thoracic and Cardiovascular Surgery. Dr. Adams has served in an advisory capacity to essentially all industry leaders in cardiovascular surgery. He also serves as the National Co-Principal Investigator of the United States FDA pivotal trial of the Medtronic CoreValve Transcatheter Aortic Valve replacement device.
Dr. Adams’ clinical interests include all aspects of heart valve surgery, with a special emphasis on mitral valve reconstruction and multiple valve surgery. His major research interests include outcomes related to mitral valve repair, novel mitral valve repair strategies, and percutaneous valve replacement. Past research honors include the Alton Ochsner Research Scholarship from the American Association for Thoracic Surgery and the Paul Dudley White Research Fellowship from the American Heart Association. He has also received honorary Professorships from Capital University in Beijing and Keio University in Tokyo. In 2009, he received the New York American Heart Association Award for Achievement in Cardiovascular Science and Medicine.
Dr. Adams received his undergraduate and medical education at Duke University and completed his internship and residency in general and cardiothoracic surgery at Brigham and Women’s Hospital and at Harvard Medical School. Dr. Adams followed that with a fellowship in London under Professor Sir Magdi Yacoub. In addition, he completed a two-year research fellowship under Professor Morris Karnovsky in the Department of Pathology at Harvard Medical School. He later served at Brigham and Women’s Hospital as the Associate Chief of Cardiac Surgery. He has been Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center since 2002.
David H. Adams, MD
Marie-Josée and Henry R. Kravis
Professor and Chairman
Department of Cardiothoracic Surgery
The Mount Sinai Medical Center
New York, NY 10029
212-659-6820
Essentially, all degenerative mitral valves are repairable. By matching echocardiographic findings to the appropriate surgical skill level required to consistently deliver a repair, valve replacement for degenerative mitral valve disease should be infrequent.
Most patients with mitral regurgitation remain asymptomatic for long periods of time. The most common presenting signs and symptoms include fatigue, decreased exercise capacity, shortness of breath, and palpitations or supra-ventricular arrhythmias such as atrial fibrillation. Auscultatory examination usually reveals a high-pitched systolic murmur radiating from the apex to the axilla. A holosytolic murmur suggests prolapse simultaneous with ejection typical of chordal rupture, whereas a murmur beginning in mid- or late systole favors billowing or chordal elongation. Radiographic findings may include left atrial and ventricular dilatation and prominent pulmonary vasculature in patients with long standing severe mitral regurgitation. The electrocardiogram may be normal, or show evidence of left atrial enlargement or atrial fibrillation.
Table 1: Selected ranges for grading severity of mitral regurgitation. Rvol, regurgitation volume, ERO, effective regurgitant orifice1, 2.
Two dimensional echocardiography with doppler is essential to determine the mechanism (dysfunction) and severity of mitral regurgitation. Semi-quantitative assessment of regurgitant flow using maximal jet length, area, and ratio of jet to left atrial area is recommended to assess the severity of mitral regurgitation1. Regurgitant jet geometry and area are assessed in multiple views and mitral regurgitation severity is graded typically as a rank order variable (e.g. 1+ trace, 2+ mild, 3+ moderate and 4+ severe mitral regurgitation). The direction of the jet provides evidence of segmental involvement as it is typically opposite to the prolapsing segment. Quantitative doppler grading of mitral regurgitation is gaining in popularity and is based on the calculation of regurgitant volume (the difference between the mitral and aortic stroke volumes) and effective regurgitant orifice (ratio of regurgitant volume to regurgitant time velocity integral). Table 1 shows the correlation between the semi-quantitative and quantitative grading of mitral regurgitation in degenerative mitral disease. Transesophageal echocardiography (TEE) is a useful adjunct to confirm the diagnosis and understand the mechanism of degenerative valve disease in the case of a non-definitive transthoracic examination. Experience is also gaining with three dimensional echocardiography in the assessment of annular geometry and leaflet dysfunction in the setting of mitral regurgitation, and can be predicted to have a more significant role in planning reparative procedures in the future.
(1) Zoghbi WA, Enriquez-Sarano M, Foster E et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003 July;16(7):777-802.
(2) Dujardin KS, Enriquez-Sarano M, Bailey KR, et al: Grading of mitral regurgitation by quantitative Doppler echocardiography: calibration by left ventricular angiography in routine clinical practice. Circulation 96(10):3409-15 1997.
In the hands of reference mitral valve-repair surgeons, 95–100% of degenerative valves are repairable, regardless of etiology; however, in the general cardiac surgical community, the repair rates are around 50%. In contrast to fibroelastic deficiency, Barlow’s valves have more complex pathology and require advanced techniques to effect a repair.
Mitral valve regurgitation is present when the valve does not close completely, causing blood to leak back into the left atrium. Mitral valve stenosis is present when the valve does not open completely, causing a relative obstruction to blood flow. Both of these conditions increase the workload on the heart and are very serious conditions. If left untreated, they can lead to debilitating symptoms including cardiac arrhythmia, congestive heart failure, and irreversible heart damage.
Figure 1: Carpentier’s functional classification. Type I, normal leaflet motion; Type II, increased leaflet motion (leaflet prolapse); Type IIIa restricted leaflet motion during diastole and systole; Type IIIb restricted leaflet motion predominantly during systole.*
Carpentier refers to the confusion surrounding classification and description of mitral valve disease as “the Babel Syndrome,” in reference to the Biblical story of what happens when workers do not speak the same language1. Degenerative mitral valve disease is the best example of this phenomenon, where terms such as prolapse, flail, partial flail, billowing, Barlow’s disease, floppy valve, and myxomatous valve disease are often used inter-changeably by different specialists, blurring the distinction between valve dysfunction and disease. Carpentier’s pathophysiologic triad1describes the inter-relationship between etiology (the cause of the disease), lesions (the result of the disease) and leaflet motion dysfunction (which results from the lesions). Carpentier’s classification of dysfunction is based on the opening and closing motions of the mitral leaflets in relation to the annular plane (Figure 1). It is in this context that degenerative mitral valve disease is best understood.
The most common leaflet dysfunction in degenerative valve disease is Type II, excess motion of the margin of the leaflet in relation to the annular plane. The lesions in degenerative valve disease that result in the Type II dysfunction are usually chordae elongation or rupture. Annular dilatation is almost always an associated finding. The most common diseases that cause degenerative mitral valve disease are Barlow’s disease and fibroelastic deficiency (Figure 2). Barlow’s disease, first described in the 1960s2, is characterized by several distinguishing features. Excess leaflet tissue with large billowing and thickened leaflets is a hallmark of Barlow’s disease, and the annular size is quite large. The chordae tendinae tend to be thickened and have a mesh type appearance in their insertion in the body of the leaflets. Chordal elongation is the most common cause of prolapse, and multiple leaflet segments are usually involved. It generally occurs in younger patients (aged
In contrast, fibroelastic deficiency is a degenerative disease of older individuals (usually >60 years of age), with a shorter history of valve regurgitation3. Rupture, often of a single chord, is the most common cause of leaflet dysfunction in fibroelastic deficiency, and in most cases the only abnormal leaflet tissue is found in the prolapsing segment. The other leaflet segments are often thin and translucent, and of normal height. The posterior annulus may be dilated, but the size of the anterior leaflet and valve are most often normal.
Type I dysfunction with normal leaflet motion and pure annular dilatation is a less common form of degenerative valve disease. It may be associated with conditions that result in significant atrial dilatation such as long-standing atrial fibrillation, or may occur in patients with connective tissue disorders.
(*) Modified from Carpentier A, Adams DH, Filsoufi F. Carpentier’s Reconstructive Valve Surgery. From Valve Analysis to Valve Reconstruction. 2010 Saunders Elsevier.
(1) Carpentier A. Cardiac valve surgery–the “French correction”. J Thorac Cardiovasc Surg1983 September;86(3):323-37.
(2) Barlow JB, Pocock WA. The significance of late systolic murmurs and mid-late systolic clicks. Md State Med J1963 February;12:76-7.
(3) Carpentier A, Chauvaud S, Fabiani JN et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg1980 March;79(3):338-48.
Portions excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
A.2 Barlow Mitral Valve Disease
The syndrome of mid-systolic click accompanying a systolic murmur was first described in the late 1800s, but it was in the early 1960s that its association with mitral regurgitation was demonstrated by Barlow and colleagues using cine-ventriculography1. Criley et al.2 correctly identified the mechanism of the regurgitation as posterior leaflet prolapse due to excess leaflet motion, coining the phrase ‘mitral valve prolapse’. Carpentier and co-workers later characterized the surgical lesions resulting from the myxoid degeneration present in Barlow’s disease, which included leaflet thickening, large redundant leaflets, chordal elongation or rupture, and annular dilatation. As the myxoid degenerative process often affects the entire valve, patients with Barlow’s disease generally have complex valve pathology and dysfunction, which is most often multisegmental (i.e. involves more than one segment of the posterior or anterior leaflet).
Clinical Presentation
Figure 1: ((a) Transesophageal echocardiography 4 chamber view showing bileaflet billowing with prolapse, large valve size, and thickened leaflet, all hallmarks of Barlow’s disease. (b) Surgical view of the same valve shows thickened tall prolapsing leaflets with excess tissue. (c) Valve has been successfully repaired after ‘complex’ bi-leaflet plasty. Repairs of this nature can only be reproducibly undertaken by reference mitral surgeons – in nonreference settings this valve would generally be replaced.
Patients with Barlow mitral-valve disease are generally adults around the age of 50 years who have known for a long period of time, often decades, that they ‘have a murmur’. Often asymptomatic, patients may have been followed by an internist for years, and referral to a cardiologist and subsequently to a cardiac surgeon is usually triggered by the development of symptoms or signs such as atrial fibrillation, shortness of breath and fatigue, or echocardiographic documentation of ventricular or atrial enlargement, or a decline in ventricular function, often accompanied by varying degrees of pulmonary hypertension. Physical examination most often reveals the presence of a mid-systolic click and a mid to late systolic murmur, which reflects the timing of prolapse in the setting of excess tissue and chordal elongation without chordal rupture (i.e. flail leaflet)2.
Echocardiographic Findings
Echocardiography is a sensitive tool in the differentiation of degenerative mitral valve disease. A striking feature of the patient with Barlow’s disease is the size of the valve apparatus – the leaflets are usually thick, bulky, elongated, and distended; the chords thickened and elongated, often mesh-like in nature; and the annulus dilated and enlarged, often times greater than 36mm in the intercommissural distance (Figure 1). The prolapse is often multisegmental, and involves both leaflets in up to 40% of patients3. The insertion of the posterior leaflet is often displaced toward the left atrium away from its normal insertion in the atrio-ventricular groove, creating a cul-de-sac at the base of the leaflet. The bodies of distended leaflet segments often billow above the plane of the annulus, and the margin of the leaflet segments prolapse in mid-systole in the setting of chordal elongation, or in early systole if chordal rupture has occurred. Calcification of the annulus and papillary muscles may be present. Real time three-dimensional echocardiography is allowing additional clarity of the segmental nature of the billowing, as well as prolapse, in Barlow’s disease4,5,6 and may play a critical role in the preoperative work up of these patients in the future.
Surgical Considerations
The complexity of surgical lesions in Barlow mitral-valve disease is consistent with the echocardiographic findings (Figure 1). Lesions include excessively thick and billowing leaflet segments, chordal elongation and chordal rupture, calcification of the papillary muscles and/or annulus with chordae restriction, and severe annular dilatation with giant valve size. It is important that the cardiologist as well as the surgeon has an appreciation for these lesions, as the complexity of techniques required to achieve a successful repair then becomes obvious in this subset of degenerative mitral-disease patients. Dealing with excess tissue height is an important consideration to reduce the likelihood of postoperative systolic anterior motion. Repair of Barlow valves is thus more complicated and, in our experience, often requires multiple different techniques and 2–3 hours to remove all of the diseased tissue, and reconstruct the leaflets to a normal configuration3.
Table 1: Targeting referral pattern to optimize repair rates.
To achieve a Barlow repair, the surgeon therefore needs to be well versed with various advanced mitral repair techniques, such as extensive leaflet resection, sliding leaflet plasty, chordal transfer, neochordoplasty, commissuroplasty, annular decalcification and use of large annuloplasty rings. Patients with advanced forms of Barlow’s disease will therefore likely have a high probability of successful valve repair only if done in reference centers by mitral subspecialists (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Barlow JB, Pocock WA, Marchand P, Denny M. The significance of late systolic murmurs. Am Heart J 1963; 66:443–452.
(2) Criley JM, Lewis KB, Humphries JO, Ross RS. Prolapse of the mitral valve: clinical and cine-angiocardiographic findings. Br Heart J 1966; 28:488–496.
(3) Adams DH, Anyanwu AC, Rahmanian PB, et al. Large annuloplasty rings facilitate mitral valve repair in Barlow’s disease. Ann Thorac Surg 2006; 82:2096–2100.
(4) Sharma R, Mann J, Drummond L, et al. The evaluation of real-time 3-dimensional transthoracic echocardiography for the preoperative functional assessment of patients with mitral valve prolapse: a comparison with 2-dimensional transesophageal echocardiography. J Am Soc Echocardiogr 2007; 20:934– 940.
(5) Patel V, Hsiung MC, Nanda NC, et al. Usefulness of live/real time threedimensional transthoracic echocardiography in the identification of individual segment/scallop prolapse of the mitral valve. Echocardiography2006; 23:513–518. (6) Muller S, Muller L, Laufer G, et al. Comparison of three-dimensional imaging to transesophageal echocardiography for preoperative evaluation in mitral valve prolapse. Am J Cardiol 2006; 98:243–248.
A.3 Fibroelastic Deficiency
In contrast to Barlow’s disease, patients with mitral regurgitation due to fibroelastic deficiency have a lack of connective tissue as the pathological mechanism that triggers leaflet and chordal thinning and eventual chordal rupture1. Carpentier’s group characterized the typical findings in fibroelastic deficiency, noting that the chordal rupture resulting in mitral valve prolapse was often isolated, usually leading to prolapse of a single leaflet segment2.
Clinical Presentation
Figure 1: (a) Transesophageal echocardiography 4 chamber view shows single segment prolapse in a normal sized valve with isolated ruptured chord. The leaflets do not billow. (b) Valve analysis shows an otherwise normal-looking valve with a single chordal rupture to the P2 segment. (c) This valve was easily repaired with a limited triangular resection and ring annuloplasty, techniques that can be reproducibly performed by most experienced cardiac surgeons.
The typical patient with fibroelastic deficiency is over the age of 60 years, and does not have a long history of a heart murmur. Often asymptomatic until the time of chordal rupture, the patient often presents with palpitations or shortness of breath of limited duration. Patients may remain asymptomatic after chordal rupture, and present as a new-onset murmur or abnormal echocardiogram, but this is less frequent than in the setting of Barlow’s disease. Physical examination is remarkable for a holosystolic murmur, often harsh in nature.
Echocardiographic Findings
In contrast to Barlow’s disease, echocardiographic signatures of fibroelastic deficiency include normal or near-normal valve size, thin leaflets and chordae, and typically single segment prolapse, most commonly of the middle scallop of the posterior leaflet (P2) (Figure 1). The prolapsing segment may appear to be distended, thickened, and elongated, while the adjacent segments appear normal in height and consistency. Billowing of nonprolapsing segments is not observed, and bi-leaflet dysfunction is uncommon.
Surgical Considerations
In contradistinction to Barlow’s disease, patients with fibroelastic deficiency often present with minimal, as opposed to excess, tissue (Figure 1), so extensive leaflet resection or complex leaflet remodeling procedures are rarely indicated. In general, a limited quadrangular or triangular resection, or simple leaflet resuspension with a chordal transfer or artificial chord, is all that is required to correct leaflet prolapse. For posterior leaflet prolapse, although the prolapsing segment may look very abnormal, the remainder of the valve is relatively unaffected, so that the surgeon does not usually require advanced techniques to achieve a successful mitral valve reconstruction.
Table 1: Targeting referral pattern to optimize repair rates.
It should, however, be noted that ‘complex’ prolapse can occur in fibroelastic deficiency, usually involving an anterior leaflet segment or a commissural segment, and in this setting more advanced techniques and surgical skill are generally required to perform a successful reconstruction. Otherwise, simple fibroelastic deficiency with P2 prolapse is a condition associated with high repair rates in most experienced surgeons’ hands, and a virtually 100% repair rate within a reference center setting with a mitral repair subspecialist (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Anyanwu AC, Adams DH. Etiologic Classification of Degenerative Mitral Valve Disease: Barlow’s Disease and Fibroelastic Deficiency. Semin Thorac Cardiovasc Surg 2007; 19:90–96.
(2) Carpentier A, Chauvaud S, Fabiani JN, et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg 1980; 79:338–348.
Numerous studies that have compared long term-survival of patients undergoing mitral valve repair or replacement have consistently shown a survival benefit with mitral valve repair. The ‘repair rate’ is thus an important variable. The ideal repair technique should be applicable to over 90% of cases. Repair rate statistics are not integral to the technique and vary from surgeon to surgeon. Unfortunately, most series do not include repair rates and prospective databases generally do not differentiate etiologies of mitral disease, such that it is not possible to accurately define repair rates for degenerative disease. We believe that the overall replacement rate in degenerative disease may be as high as 50%. In a review of United States practice in 1999 and 2000, 42.4% of patients having isolated mitral valve surgery for valve regurgitation had a valve repair (all etiologies of mitral disease)1. Similarly, in the United Kingdom, 35% of mitral procedures were repairs in 2000-20012. In the United Kingdom, more mechanical mitral valve replacements were performed than mitral repairs (ratio 6:5). We believe that as degenerative disease often occurs in young patients (who are the usual candidates for mechanical valves), and as the incidence of rheumatic disease has declined substantially in western countries, a considerable number of these mechanical mitral valve replacements are likely performed for degenerative disease. Indeed a review of contemporary mitral valve replacement literature shows substantial proportions of replacements for degenerative disease. For example, Bouchard and associates3 in a series examining outcomes of mitral valve replacement, include 213 replacements for degenerative disease over a ten-year period. In another recent study, Yun et al4 randomized 47 patients over two years to two forms of chordal sparing valve replacement; 31 of these patients had degenerative disease. Finally in a series of 154 bioprosthetic implants reported by Rizzoli et al, 34 were performed for degenerative disease5. Repair rates in large published series generally range from 85% to 90%, although most include historical patients from the 1980s. Our philosophy is that repair should be attempted in all degenerative valves. Using this approach we have achieved a 99.5% repair rate over a 4 year period. For mitral valve repair to be the standard of care for degenerative disease, it should be available and applicable to all patients. Certainly any surgeon performing surgery for asymptomatic degenerative disease should have > 95% repair rate for the lesion present, as mitral repair is the only therapy currently advisable in this group6. Current national repair rates, however, suggest that there remains a considerable body of surgical practice that has not embraced systematic repair of degenerative valves.
(1) Savage EB, Ferguson TB, Jr., DiSesa VJ. Use of mitral valve repair: analysis of contemporary United States experience reported to the Society of Thoracic Surgeons National Cardiac Database. Ann Thorac Surg 2003 March;75(3):820-5.
(2) Keogh BE, Kinsman R. Fifth National Adult Cardiac Surgical Database Report 2003. Henley-on-Thames: Dendrite; 2004.
(3) Bouchard D, Pellerin M, Carrier M et al. Results following valve replacement for ischemic mitral regurgitation.Can J Cardiol 2001 April;17(4):427-31.
(4) Yun KL, Sintek CF, Miller DC et al. Randomized trial comparing partial versus complete chordal-sparing mitral valve replacement: effects on left ventricular volume and function. J Thorac Cardiovasc Surg 2002 April;123(4):707-14.
(5) Rizzoli G, Bottio T, Vida V et al. Intermediate results of isolated mitral valve replacement with a Biocor porcine valve. J Thorac Cardiovasc Surg 2005 February;129(2):322-9.
(6) Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005 February 5;365(9458):507-18.
B.2 Long Term Survival
When interpreting data on long-term survival, it should be appreciated that available data refer to the outcomes of mitral repair and cardiac surgery as practiced 10 to 20 years previously1. Cardiac surgery has, however, since improved in several ways; for example, the widespread adoption of blood cardioplegia has likely reduced the ventricular damage during surgery which in turn will impact long-term survival (as left ventricular function is a major determinant of long-term survival). There is therefore no way of knowing the long-term survival outcomes of mitral valve surgery as currently practiced. Based on existing data, it appears that if surgery is undertaken before onset of symptoms and where left ventricular function is preserved, the life expectancy should be similar to that of the general population2, 3, 4. When significant symptoms of heart failure have developed (NYHA III – IV) before mitral valve surgery is undertaken, the long term survival is significantly reduced (Figure 1), regardless of the left ventricular function5. Similarly, patients with an impaired left ventricular ejection fraction at time of surgery have a reduced long-term survival (Figure 2).
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
(1) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(2) Enriquez-Sarano M. Timing of mitral valve surgery. Heart 2002 January;87(1):79-85.
(3) Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation 2001 September 18;104(12 Suppl 1):I1-I7.
(4) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(5) Tribouilloy CM, Enriquez-Sarano M, Schaff HV et al. Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation 1999 January 26;99(3):400-5.
(*) Modified from Tribouilloy CM, Enriquez-Sarano M, Schaff HV, et al: Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications.Circulation 99 (3):400-5, 1999. Lippincott Williams & Wilkins
(**) Modified from Enriquez-Sarano M, Tajik AJ, Schaff HV, et al: Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation; 90(2):830-7, 1994. Lippincott Williams & Wilkins
B.3 Failures and Re-operations
Figure 1: Outcome after mitral valve repair. A,freedom from reoperation in patients with posterior, anterior and bileaflet prolapse. B,freedom from recurrent moderate (3+) or severe (4+) MR according to prolapsing leaflet. AL, anterior leaflet, PL, posterior leaflet, BL, bileaflet prolapse.*
Failure of repair, defined by recurrence of moderate or severe mitral regurgitation, or re-operation for mitral regurgitation are principal endpoints to evaluate the long-term outcomes of mitral valve repair. Failure rates of mitral valve repair are determined principally by the original dysfunction (posterior leaflet, anterior leaflet and bi leaflet) and by repair technique. The longest term follow-up available is for conventional ‘Carpentier’ techniques. Braunberger and colleagues1reported in 2001 on the long term outcomes of 162 non-rheumatic patients (of whom 90% were degenerative) who underwent a Carpentier repair between 1970 and 1984. They observed that 97% of patients with posterior leaflet, 86% with anterior leaflet and 83% of patients with bileaflet prolapse were free of re-operation at 20 years (Figure 1a). They also found 74% were free from cardiac events at 20 years. The difference between freedom from reoperation and freedom from cardiac event rates, however highlights the limitations of re-operation rate as an outcome measure for mitral repair. Because the decision to undergo reoperation is physician and patient dependent, at least some of those patients with cardiac symptoms had recurrent mitral regurgitation, but never underwent reoperation. In the absence of echocardiographic follow-up, there is no way of quantifying the true long-term failure rate. David and colleagues2 also presented 20 year follow-up for patients (operated between 1981 and 2001) using a variety of repair techniques, including conventional Carpentier techniques and gortex neochordoplasty, and found 96%, 88% and 94% freedom from re-operation rates at 12 years for posterior, anterior and bileaflet prolapse respectively. They also reported on freedom from moderate or severe mitral regurgitation – 80%, 65% and 67% respectively at 12 years (Figure 1b) – however, follow-up echocardiographic data was available for only half of the patients. The lack of systematic echocardiographic follow-up is the major limiting factor in determining the true durability of all mitral repair techniques3; most series have focused on survival and re-operation rates which may not necessarily be reflective of the durability of repair.
Figure 2: Freedom from recurrent mitral regurgitation after mitral valve repair. Kaplan-Meier estimates of freedom from non-trivial MR (MR>1/4) and failing repair (MR>2/4). A linearized recurrence rate per year of 8.3% is found for MR grade >1/4. The rate grade >2/4 is 3.4%.**
The most complete and elaborate follow-up for mitral repair in contemporary literature is probably the series of Flameng and associates4 who report a series of 242 consecutive mitral repairs with serial follow-up echocardiography done at 6 month intervals. They found a freedom from moderate or severe mitral regurgitation of 71% at 7 years and found that new recurrent mitral regurgitation appeared at a rate of 3.7% per year (Figure 2). The data of Flameng and colleagues4 suggest that durability of many mitral repairs is limited; the linear recurrence rate implies that recurrent mitral regurgitation is likely a reflection of progression of underlying valve disease. This hypothesis is supported by data from mitral re-operations after previous repair, as the previous repairs are found to be intact in two-thirds of patients, with recurrent regurgitation usually due to new valve lesions (chordal rupture, fibrosis, calcification, leaflet perforation)5. Technical failure can be a major cause of recurrence, particularly with early failures6, but should be minimal in experienced hands. Some surgical factors that predispose to recurrence of mitral regurgitation include the non-use of an annuloplasty ring, and the technique of chordal shortening.
The edge-to-edge technique is a relatively new repair strategy with limited follow-up compared to Carpentier techniques. One large published series from De Bonis and colleagues7 included 133 patients, followed for a median of 3 years, in whom anterior leaflet prolapse was treated with the edge-to-edge technique; they estimated a 10 year freedom from re-operation of 96.5%, but do not include data that allow computation of the freedom from mitral regurgitation rate.
(1) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(2) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(3) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(4) Flameng W, Herijgers P, Bogaerts K. Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 2003 April 1;107(12):1609-13.
(5) Cerfolio RJ, Orzulak TA, Pluth JR, Harmsen WS, Schaff HV. Reoperation after valve repair for mitral regurgitation: early and intermediate results. J Thorac Cardiovasc Surg 1996 June;111(6):1177-83.
(6) Shekar PS, Couper GS, Cohn LH. Mitral valve re-repair. J Heart Valve Dis 2005 September;14(5):583-7.
(7) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(*) Modified from A, Braunberger E, Deloche A, Berrebi A, et al: Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 104(12 Suppl 1):I8-11 2001 Lippincott Williams & Wilkins and B, Reprinted from J Thorac Cardiovasc Surg 130(5), David TE, Ivanov J, Armstrong S, et al, A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse, 1242-9, Copyright 2005, with permission from the American Association for Thoracic Surgery.
(**) Modified from Flameng W, Herijgers P, Bogaerts K: Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 107(12):1609-13 2003. Lippincott Williams & Wilkins
B.4 Operative Mortality and Morbidity
The operative mortality rate for mitral valve surgery has steadily declined over the past decade, with the current mortality rates reported to the Society of Thoracic Surgery Database in the region of 1.5% for mitral valve repair and 5.5% for mitral valve replacement. There is a suggestion that centers doing large numbers of repairs for degenerative mitral valve disease deliver especially low mortality. For example, David and colleagues1 had only five operative deaths in a series of 701 repairs over 20 years, De Bonis and associates2 reported 2 deaths in a series of 738 repairs over 13 years, while Gillinov and colleagues reported 3 deaths in 1072 repairs for degenerative disease over a-12 year period3. Performing a tricuspid repair at time of mitral valve repair does not appear to increase mortality risk4, but mortality rises to above 3% with concomitant coronary artery bypass surgery5. Complications rates are low for elective mitral valve repair for degenerative valve disease. In our series of 67 consecutive Barlow patients we observed one patient with mediastinitis, one re-operation for bleeding and no strokes6. Major neurological complications should be uncommon in the 1% range, although there are recent data suggesting that patients having surgery via minimally invasive approaches may have a higher incidence of stroke7. Meticulous myocardial preservation is imperative to obtaining good results as the period of aortic clamping is lengthy for complex repairs (in our Barlow’s series we had a mean cardiopulmonary bypass time of 191 minutes)6.
(1) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(2) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(3) Gillinov AM, Cosgrove DM, Blackstone EH et al. Durability of mitral valve repair for degenerative disease. J Thorac Cardiovasc Surg 1998 November;116(5):734-43.
(4) Dreyfus GD, Corbi PJ, Chan KM, Bahrami T. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann Thorac Surg 2005 January;79(1):127-32.
(5) Gillinov AM, Blackstone EH, Rajeswaran J et al. Ischemic versus degenerative mitral regurgitation: does etiology affect survival? Ann Thorac Surg 2005 September;80(3):811-9.
(6) Adams DH, Anyanwu A, Rahmanian PB, Abascal V, Salzberg SP, Filsoufi F. Larger Annuloplasty Rings Facilitate Mitral Valve Repair in Barlow’s Syndrome. Ann Thorac Surg. 2006;82:2096-2101.
(7) Cheema FH, Martens TP, Duong JK et al. Comparison of Minimally Invasive Versus standard Approach to Mitral Valve Surgery: Results from an Audited State-Wide mandatory Database. Ann Thorac Surg. In press 2006.
Most complex mitral valve repair surgery can be performed through a 4 inch sternotomy.
Our Minimally Invasive Heart Surgery Center offers minimally invasive heart valve surgery to selected patients. Not all patients are suitable for minimally invasive surgery. Patients who require additional cardiac procedures like coronary artery bypass surgery, elderly patients, patients with very diseased arteries, and patients with a very weakly contracting heart will not be suitable for this approach. Our paramount objective is to ensure a good valve repair, with no residual leakage, at a low operative risk.Our surgeons will only perform a repair through a small incision when they believe they can do a good quality valve repair at a low risk to the patient; if the valve disease is complicated (as assessed by the echocardiogram) then we recommend a full incision as we believe a larger scar is preferable to an imperfect repair.
Ask the surgeon if this is an option for you.
Different Approaches to Minimally Invasive Heart Surgery
Dr. David Adams and Dr. Ani Anyanwu use special instruments to perform minimally invasive heart valve surgery.
The term “minimally invasive surgery” covers a spectrum of approaches. The goal is to perform surgery through a smaller incision without compromising the safety and long-term results of conventional mitral valve repair. The advantage of a small incision is mainly cosmetic (the scars are smaller and less visible). In some patients, the pain after surgery may be reduced and recovery from surgery is faster when surgery is done through a smaller incision. Operating through small incisions is however more technically demanding and in some cases could reduce the safety of the procedure. This page describes the various incisions, and you can read more about the associated benefits and disadvantages of each.
Lower Sternotomy
Dr. David Adams with Mary D., five weeks after surgery, whose minimally invasive valve repair was performed with a sternotomy.
In this approach the surgeon makes a 4 inch incision over the lower aspect of the midline of the chest and divides only the lower portion of the breast bone to gain access to the valve. This limits the actual amount of opening, and thus chest wall trauma. Through this incision we can easily access the heart and all the major vessels and can perform most complex mitral valve repairs along with aortic valve replacement or coronary artery bypass grafting. This incision has the advantage that if the surgeon encounters problems, he or she can easily extend the incision and divide the remaining breast-bone and convert to the standard approach. When fully healed the lower sternotomy scar is concealed by clothing, even when the patient wears low-necked clothing. In some women the scar is well concealed by their brassiere. It is the most flexible approach to the heart, and it is the approach we use in most patients.
Mini-Thoracotomy
Mitral valve surgery can be carried out through a 2-3 inch incision, usually under the right breast, which allows the surgical team to see and work on the mitral valve directly. The patient is placed on the heart-lung machine either through the same chest incision or through the vessels in the groin via a 1 inch incision. Durable, simple and more complex mitral repairs can be performed, eliminating mitral regurgitation in a wide range of patients.
Thoracotomy
Dr. David Adams shows a thoracotomy incision from a minimally invasive heart valve repair, eight days after surgery.
In this approach the surgeon makes a 4 to 6 inch incision in the right side (instead of middle) of the chest and gains access to the heart by going through the ribs. Some women prefer this incision because the scar may be placed underneath the breast crease and is therefore largely concealed. Access to the heart may be difficult in some cases making it more difficult to achieve a perfect repair.
Low Skin Incisions
Patients who are concerned about cosmesis, but who are not suitable for minimally invasive surgery, can request a low incision. The surgeon can make the standard skin incision start an inch lower and yet perform full division of the breastbone. The scar will therefore not be visible when wearing normal clothing. Patients who cannot have a minimally invasive operation, but who are concerned about the scar, can also request the services of our plastic surgeon to cosmetically close the incision.
Robotic Surgery and Endoscopic Surgery
In these approaches the surgeon performs the operation through several mini-incisions or “port sites”, the largest being about 2 inches. Robotic mitral valve repair is performed using the assistance of a ‘robot’ and specially designed instruments to perform the operation. The surgeon sits at a console and controls the instruments which are mounted on the arms of a robot by another surgeon. Endoscopic mitral valve repair is performed using long instruments placed through the port sites. The patient is placed on the heart-lung machine via blood vessels in the groin. In both cases, the surgeon uses video cameras to see inside the chest cavity.
Although cosmetically superior, these approaches limit the complexity of repair that can be undertaken by the surgeon, and in some cases may compromise on the quality of repair. For this reason, we do not offer these two approaches at Mount Sinai as we cannot guarantee the same high standards of mitral valve repair as we can with other approaches.
B. Non-surgical Management
Asymptomatic mitral regurgitation and
Medical management according to the effective regurgitant orifice (ERO)
Figure 1: Cardiac events among patients with asymptomatic mitral regurgitation and medical management according to the effective regurgitant orifice (ERO). Kaplan-Meier estimates of means ± standard deviation. Cardiac events were defined as death due cardiac causes, congestive heart failure, or new onset of atrial fibrillation.*
As current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated cohorts. Additionally, before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation. Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death. Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6. Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1). Other risk factors for cardiovascular morbidity include atrial fibrillation, left atrial enlargement, age > 50 years and thickening of mitral leaflets7 – presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
It should be emphasized that the alternative to surgical therapy is, strictly speaking, not medical therapy, but observation, as there are no pharmacological options for treatment of severe mitral regurgitation. Data supporting the role of any medical treatment – particularly vasodilators – in the management of severe regurgitation due to degenerative mitral valve disease is scant11. Indeed it has been suggested that vasodilator therapy can lead to paradoxical worsening in mitral regurgitation by shifting the prolapse earlier in the cardiac cycle12. Vasodilator therapy can also mask left ventricular dysfunction and result in (potentially deleterious) delay to mitral valve surgery. According to current guidelines, there is little role for pharmacological treatment in the management of severe mitral regurgitation1.
Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions
Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC
and
Article Curator: Aviva Lev-Ari, PhD, RN
The Curator recommends the e-Reader to read the following book on Surgical Complications:
Complications
“Essential Reading For Anyone Involved In Medicine”–Amazon.com – 2002
IIb. PAD Endovascular Interventions: Carotid Artery Endarterectomy
III. Incidence of Sepsis (circulation infection with serious consequences)
UPDATED 11/2/2013
As minimally interventional techniques improve, patients are offered a choice of invasive surgical remedies or less invasive procedures (video assisted, robotic, or percutaneous). The decision should not rest on the size of the scar or even the up front risk and discomfort, but rather should weigh all aspects of the risks and benefits. In addition to the risks and benefits for the current problem, one should also consider why the problem occurred and its likelihood of recurrence. Open chest surgery has a clear disadvantage when it comes to recurrences, as the scars from first surgery interfere with second surgery. Opening the chest (sternotomy) for a second or third time poses elevated risks analyzed herein. This article reviews data from major centers addressing the risks from repeat sternotomy and from minimally invasive cardiovascular surgeries. Any invasion of the body elevates risk of infection, which can lead to sepsis and possible death, so that risk is also addressed.
This article addresses specific reports of complications but does not cover numerous other complications that may occur, such as lung collapse, cardiogenic shock, blood loss, local infection, emboli, thrombus, stroke.
Read at the 90th Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 1–5, 2010. Received for publication April 6, 2010; revisions received July 19, 2010; accepted for publication July 30, 2010.
doi:10.1016/j.jtcvs.2010.07.086
Particular attention to protective strategies should be considered during reoperative sternotomy among patients with multiple previous sternotomies, previous mediastinal radiotherapy, and those with patent internal thoracic artery grafts. (J Thorac Cardiovasc Surg 2010;140:1028-35)
Of the 2555 patients,
1537 (60%) had undergone previous coronary artery bypass grafting,
Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN 55905, USA.
Abstract
OBJECTIVES:
A variety of protective strategies during repeat sternotomy been proposed; however, it remains unclear for which patients they are warranted.
METHODS:
We identified adults undergoing repeat median sternotomy for routine cardiac surgery at our institution between January 1, 1996, and December 31, 2007. The operative notes and perioperative outcomes were reviewed.
RESULTS:
Of the 2555 patients, 1537 (60%) had undergone previous coronary artery bypass grafting, 700 (27%) previous mitral valve surgery, and 643 (25%) previous aortic valve replacement (AVR). Sixty-one patients (2%) had prior mediastinal radiotherapy, and 424 (17%) had more than one previous sternotomy. In 231 patients, 267 injuries (9.0%) occurred. Injury occurred during sternotomy in 87 patients (33%) and during prepump dissection in 135 (51%). The hospital mortality rate was 6.5% among those without injury and 18.5% among those with injury (P < .001); when injury occurred during sternal division, the mortality rate was 25%. Injuries were more common after previous coronary artery bypass grafting (11% with previous coronary artery bypass grafting vs 7% without, P = .0012) but not previous AVR, mitral valve surgery, or aortic surgery. Injury was also more common when the current operation was AVR (10% with AVR vs 8% without, P = .04) or aortic surgery (14% vs 8%, P = .004). On multivariate analysis, previous radiotherapy (odds ratio, 4.9), a greater number of previous sternotomies (odds ratio 1.7), and a patent internal thoracic artery (odds ratio, 1.8) predicted injury. Injury was an independent risk factor of hospital death (odds ratio, 2.6).
CONCLUSIONS:
Particular attention to protective strategies should be considered during reoperative sternotomy among patients with multiple previous sternotomies, previous mediastinal radiotherapy, and those with patent internal thoracic artery grafts.
Previous operation No injury (n 1/4 2324) Injury (n 1/4 231) P value
CABG 1375 (59.2%) 162 (70.1%) .001
Aortic valve surgery 586 (25.2%) 57 (24.7%) .857
Mitral valve surgery 645 (27.8%) 55 (23.8%) .200
Tricuspid valve surgery 64 (2.8%) 9 (3.9%) .320
Aorta surgery 167 (7.2%) 20 (8.7%) .413
Current operation No injury (n 1/4 2324) Injury (n 1/4 231) P value
CABG 897 (38.6%) 104 (45.0%) .056
Aortic valve surgery 1020 (43.9%) 118 (51.1%) .036
Mitral valve surgery 821 (35.3%) 80 (34.6%) .833
Tricuspid valve surgery 414 (17.8%) 52 (22.5%) .078
Aortic surgery 232 (10.0%) 37 (16.0%) .004
DISCUSSION
The results of the present study have confirmed the significant risk of cardiovascular injury during reoperative cardiac surgery. The death rate from such injury can be 10-30%, particularly when occurring during division of the sternum. These risks are greatest among patients with multiple previous sternotomies or prior chest radiotherapy.
Current PROTOCOL at Virginia University, now suggested to be considered for adoption @Mayo Clinic:
The Mayo Clinic’s Authors write: Our findings are more consistent with those reported by Roselli and colleagues.2 The explanation of these institutional differences is unclear, although a number of practice differences are likely present between these institutions in terms of both patient substrate and surgical practice. Compared with the series from the University of Virginia, the Mayo series we have reported represents a greater percentage of total cases performed at the institution (13.5% vs 7.8%), with a somewhat greater percentage of those reoperations being for CABG (41% vs 60%). In the Mayo series, a lower percentage were first-time repeat sternotomies (83% vs 90%) and a greater percentage were the fourth time or more (2.7% vs 1.1%).
The incidence of previous radiotherapy in the University of Virginia series was not reported.
It is also unclear to what degree the differences in surgical practice, including the role of the assistant surgeons in performing the repeat sternotomy, could account for these differences. In the present retrospective study, we were unable to demonstrate an effect of experience or expertise in either the occurrence of injury or the outcome. However, it is clear to all practicing surgeons that, when injury occurs, the judgment and expertise of the operating surgeon is critical to expeditious institution of CPB or other ‘‘rescue’’ maneuvers.
Perhaps of more practical value and broad applicability, however, is the standardized approach to repeat sternotomy advocated by the group at the University of Virginia, including routine preoperative CT scanning if the procedure is the third or fourth sternotomy and insertion of a femoral arterial line by which emergent percutaneous arterial inflow cannulation can be accomplished, if necessary. In their series, emergent institution of CPB using the femoral route was instituted in 1.8% of reoperative patients, constituting 19% of the patients with injury. Most notably, in their series, no deaths occurred among these patients. Serious consideration should be given to adopting such protocols.
Our high mortality rate associated with SVG injury during sternotomy, however, supports the recommendation by others to carefully assess the course of bypass grafts by preoperative angiography. Routine preoperative CT imaging of all patients with more than one previous sternotomy has been advocated by Morishita and colleagues,3 with a demonstrable reduction in operative complications. Roselli and colleagues2 identified a lack of preparative imaging as the most common ‘‘lapse’’ in the preventive strategy among patients with injury. Our data suggest that CT scanning might be particularly helpful in the subset of patients with multiple previous sternotomies or radiotherapy and would support the institution of a policy of routine scanning for these patients.
FIGURE 1. Hospital mortality according to emergent cardiopulmonary bypass (CPB) in The Journal of Thoracic and Cardiovascular Surgery c November 2010, pp. 1032
TABLE 5. Postoperative results
No injury (n 1/4 2324) — Injury (n 1/4 231) — P value
Postoperative transfusion (U)
PRCs 4.5 7.2 6.5 8.9 .046
ICU stay (h) 102.3 228.6 146.3 +/- 346.9 <.001
Reoperation for bleeding 127 (5.5%) 21 (9.1%) .024
The Journal of Thoracic and Cardiovascular Surgery c November 2010, pp. 1032
Independent predictors for injury during repeat median sternotomy
The structures injured and the timing of injury in our study were similar to those reported by Roselli and colleagues.2 Bypass grafts were the most commonly injured and, perhaps in contrast to expectations, most injuries occurred during dissection, not during sternal division. Unlike their study, however, we found injury during sternal division to carry a greater mortality risk. We observed a remarkably high mortality rate associated with injury to the right ventricle, as did Roselli and colleagues.2 This may be particularly true in the presence of pulmonary hypertension, when attempts to repair the injury are hampered by inadequate access, progressive tearing of the ventricle secondary to traction injury, and what can be a relatively thin and friable free wall. The incidence of injury to the Internal thoracic artery (ITA) in our series (4.9%) was comparable to the 4.4%–5.3% reported by other investigators.11-14 Because the ITA was damaged more often during prepump dissection (20.7%) than during re-entry (11.5%), these data support the trend to avoid dissecting and isolating the ITA during AVR after previous CABG.12,13
FOUR CONCLUSIONS
1. On the basis of these data, we would advocate preoperative axial CT imaging to define the proximity of cardiovascular structures to the sternum of patients who have undergone more than one previous sternotomy and those who have undergone radiotherapy because these patients statistically have the greatest risk of injury.
2. We would also advocate considering percutaneous or open access of the femoral vessels, if not the institution of CPB, before sternotomy in these same patients, as well as those with significant pulmonary hypertension.
3. Because injury is common during prepump dissection, we support a philosophy of leaving patent ITA grafts undisturbed by attempts to gain control during AVR after previous CABG.
4. Finally, given the mortality rate associated with graft injury, patients with previous CABG should be considered for graft angiography or high-resolution CT.
Summary
This is a very important study on the Outcomes and the Complications involved in Cardiac Surgery @Mayo Clinic.
Study’s Objectives: A variety of protective strategies during repeat sternotomy been proposed; however, it remains unclear for which patients they are warranted.
Authors @Mayo Clinic reported:
We were unable to definitively assess the effect of any specific protective strategies on the incidence of injury. Because we do not have standardized or uniform prospective institutional policies in this regard, it was not possible to account for the confounding factor of the clinician’s judgment in the decision to use these strategies in particularly highrisk patients.
Our high mortality rate associated with saphenous vein graft (SVG) injury during sternotomy, however, supports the recommendation by others to carefully assess the course of bypass grafts by preoperative angiography.Routine preoperative CT imaging of all patients with more than one previous sternotomy has been advocated by Morishita and colleagues,3 with a demonstrable reduction in operative complications.
The reader is advised to review another article Co-Curated by us on the following related study by Mayo Clinic researches, This article examines 10-year to 15-year survivals from arterial bypass grafts using arterial vs saphenous venous grafts.
In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery,
arterial grafting of the non-left anterior descending vessels conferred a survival advantage at 15 years compared with Saphenous Venous grafting (SVG).
It is still unproven whether these results apply to higher-risk subgroups of patients.
Impact of Intra-procedural Stent Thrombosis during Percutaneous Coronary Intervention: Insights from the CHAMPION PHOENIX Trial ONLINE FIRST
Philippe Généreux, MD1; Gregg W. Stone, MD1; Robert A. Harrington, MD4; C. Michael Gibson, MD5; Ph. Gabriel Steg, MD6; Sorin J. Brener, MD10; Dominick J. Angiolillo, MD, PhD11; Matthew J. Price, MD12; Jayne Prats, PhD13; Laura LaSalle, MPH2; Tiepu Liu, MD, PhD12; Meredith Todd, B.Sc12; Simona Skerjanec, Pharm.D12; Christian W. Hamm, MD14; Kenneth W. Mahaffey, MD4; Harvey D. White, DSc15; Deepak L. Bhatt, MD, MPH16
Objective We sought to evaluate the clinical impact of intra-procedural stent thrombosis (IPST), a relatively new endpoint.
Background In the prospective, double-blind, active-controlled CHAMPION PHOENIX trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.
Methods An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment anytime during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.
Results IPST developed in 89 patients (0.8%), including 35/5470 (0.6%) and 54/5469 (1.0%) in the cangrelor and clopidogrel arms, respectively (OR [95%CI] = 0.65 [0.42,0.99], p=0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new onset out-of-lab stent thrombosis [ARC]) at 48 hours and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, P<0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.
Conclusion In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous ADP antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 hours and 30 days.
Bleeding and Vascular Complications at the Femoral Access Site Following Percutaneous Coronary Intervention (PCI): An Evaluation of Hemostasis Strategies
Dale R. Tavris, MD, MPH1, Yongfei Wang, MS2, Samantha Jacobs, BS1, Beverly Gallauresi, MPH, RN1, Jeptha Curtis, MD2, John Messenger, MD3, Frederic S. Resnic, MD, MSc4, Susan Fitzgerald, MS, RN5
Authors Affiliation
From the 1US Food and Drug Administration (FDA), Silver Spring, Maryland, 2Yale University, New Haven, Connecticut, 3University of Colorado, Boulder, Colorado, 4Brigham and Women’s Hospital, Boston, Massachusetts, and 5the American College of Cardiology, Bethesda, Maryland.
Abstract: Background. Previous research found at least one vascular closure device (VCD) to be associated with excess vascular complications, compared to manual compression (MC) controls, following cardiac catheterization. Since that time, several more VCDs have been approved by the Food and Drug Administration (FDA). This research evaluates the safety profiles of current frequently used VCDs and other hemostasis strategies. Methods. Of 1089 sites that submitted data to the CathPCI Registry from 2005 through the second quarter of 2009, a total of 1,819,611 percutaneous coronary intervention (PCI) procedures performed via femoral access site were analyzed. Assessed outcomes included bleeding, femoral artery occlusion, embolization, artery dissection, pseudoaneurysm, and arteriovenous fistula. Seven types of hemostasis strategy were evaluated for rate of “any bleeding or vascular complication” compared to MC controls, using hierarchical multiple logistic regression analysis, controlling for demographic factors, type of hemostasis, several indices of co-morbidity, and other potential confounding variables. Rates for different types of hemostasis strategy were plotted over time, using linear regression analysis.Results. Four of the VCDs and hemostasis patches demonstrated significantly lower bleeding or vascular complication rates than MC controls: Angio-Seal (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.65-0.70); Perclose (OR, 0.54; CI, 0.51-0.57); StarClose (OR, 0.77; CI, 0.72-0.82); Boomerang Closure Wire (OR, 0.63; CI, 0.53-0.75); and hemostasis patches (OR, 0.70; CI, 0.67-0.74). All types of hemostasis strategy, including MC, exhibited reduced complication rates over time. All trends were statistically significant except one. Conclusions. This large, nationally representative observational study demonstrated better safety profiles for most of the frequently used VCDs, compared to MC controls.
The benefits of the transradial approach have clearly been documented in numerous studies in the past ten years.1–9 Access site bleeding complication rates are lower and early ambulation results in a significant reduction in patient morbidity and a lower total procedure cost.3,4 Both patients undergoing the procedure and staff caring for these patients overwhelmingly prefer the transradial approach.10
As a result of these benefits, there has been an increase in the use of the radial artery for interventional procedures worldwide in the past several years. This experience has led to an understanding of the problems and complications that can result from the transradial approach. The purpose of the present manuscript is to review these issues. Radial artery occlusion. Although this complication is a major concern, the consequences of radial artery occlusion are usually benign. The dual blood supply to the hand is an extremely protective mechanism (Figure 1). Hand ischemia with necrosis has occurred following prolonged cannulation of the radial artery for hemodynamic monitoring in critically ill patients; however, this complication has not been reported thus far after transradial coronary procedures.
The absence of ischemic complications is largely the result of the original recommendation by Kiemeneij that the transradial procedure be performed only in patients with a documented patent ulnar artery and palmar arch.1 This has traditionally been evaluated using the Allen’s test, but ultrasound, Doppler, and plethysmography prior to the procedure are more accurate methods.11
Plethysmography is probably the simplest and most effective method. A pulse oximetry test is performed with the probe placed on the patient’s thumb (Figure 2). The persistence of waveform and high oximetry readings after digital occlusion of the radial artery is very strong evidence that the patient will have sufficient collateral flow to prevent hand ischemia if the radial artery should become occluded as a result of the procedure. Barbeau has demonstrated the reappearance of the waveform and a high oximetry reading two minutes after initial negative results.11 This delayed recruitment of collaterals may be an additional explanation for the absence of hand ischemia with radial occlusion.
Several variables influence the incidence of radial artery occlusion. Adequate anticoagulation is extremely important. This is usually not an issue in patients undergoing interventional procedures, but the incidence of radial occlusion was as high as 30% in patients receiving only 1,000 units of heparin during diagnostic catheterization.12 The incidence of radial occlusion is reduced significantly by administering at least 5,000 units of heparin during the procedure.12,13 Due to this risk of radial occlusion, we tend to reserve the use of the radial artery for interventional procedures and “look-see” diagnostic catheterization. Elective diagnostic catheterizations are performed transradially only when there is an increased risk of femoral complications.
Catheter size has been shown to be an important predictor of post-procedure radial artery occlusion. Saito has studied the ratio of the radial artery internal diameter to the external diameter of the arterial sheath.14 The incidence of occlusion was 4% in patients with a ratio of greater than 1, as compared to 13% in those with a ratio of less than 1. Radial procedures have traditionally been performed using 6 Fr catheters, and most patients have an internal radial artery diameter larger than the 2.52 mm external 6 Fr sheath diameter.14 The incidence of radial occlusion following 6 Fr procedures is less than 5%, but the rate increases with larger sheath sizes.4,13 Virtually all interventional procedures can now be performed through large-bore, 6 Fr guide catheters, and larger-sized catheters are rarely necessary. For straightforward procedures, 5 Fr guide catheters may be utilized and are particularly useful in smaller women.
When the radial artery is utilized for hemodynamic monitoring in critically ill patients, the incidence of radial occlusion is significantly higher in patients with cannulation times greater than 24 hours, as compared to those under 20 hours.15 Since catheters are virtually always removed at the conclusion of a catheterization or interventional procedure, the time of cannulation may not be a factor. However, prolonged post-procedure compression times, particularly with high pressure using a mechanical device, may be a factor. We use sufficient pressure only to achieve hemostasis and try to remove the device as quickly as possible. Even in patients with intensive anticoagulation, it is rarely necessary to maintain mechanical compression for longer than one to two hours. A compression dressing using non-occlusive pressures can then be applied.
In summary, post-procedure radial occlusion occurs only in a small percentage of patients and is virtually always asymptomatic because of the dual blood supply to the hand. Patients with generalized vascular disease, diabetes mellitus, and those undergoing repeat procedures are more susceptible. The incidence can be minimized with appropriate anticoagulation, proper sheath selection, and avoiding prolonged high-pressure compression following the procedure. Non-occlusive radial artery injury. Recent studies have demonstrated that permanent radial artery injury without occlusion may occur following transradial intervention in some patients. Mean radial artery internal diameter as measured by ultrasound was smaller in patients undergoing repeat transradial interventional procedures as compared to the initial procedure.16 This smaller diameter was not present on the day following the procedure, but developed during a mean follow up of 4.5 months. Wakeyama et al. demonstrated with intravascular ultrasound that this progressive narrowing is due to intimal hyperplasia, presumably induced by trauma from the cannulation sheath or catheter.17 The studies in our laboratory show that this hyperplasia is usually segmental rather than diffuse and is not present in all patients with a previous transradial procedure (Figure 3). The incidence of subsequent intimal hyperplasia in patients undergoing radial procedures is yet to be determined.
The ramifications of this injury are important not only in patients undergoing repeat interventional procedures, but also in patients in whom the radial artery may be used as a conduit for coronary artery bypass surgery. At our center, this is not an issue as most procedures are performed from the right radial artery and surgeons use the left radial artery for bypass graft purposes. At present, it would seem prudent not to use a radial artery that previously has been used for a catheterization as a bypass graft. Radial artery spasm. Much of the morbidity of the transradial procedure is related to vasospasm induced by the introduction of a sheath or catheter into the radial artery. The vessel has a prominent medial layer that is largely dominated by alpha-1 adenoreceptor function.18 Thus, increased levels of circulating catecholamines are a cause of radial artery spasm. Local anesthesia and adequate sedation to control anxiety during catheter insertion are important preventative measures.
It has been demonstrated in isolated radial artery ring segments that nitroglycerin and verapamil are effective agents in preventing arterial spasm.19 Indeed, a vasodilator cocktail consisting of 3–6 mg of verapamil injected intra-arterially prior to sheath insertion is extremely effective in preventing radial artery spasm. The effect of the drug is immediate and significant arterial dilatation can be seen within minutes of its administration (Figure 4).
Intra-arterial verapamil and nitroglycerin have virtually eliminated vasospasm as a cause of significant morbidity of the procedure. It is now possible to perform transradial procedures using short sheaths and arm discomfort generally occurs only in patients with very small or tortuous radial arteries, particularly if guide catheter manipulation is excessive.
Spasm distal to the access site may be a cause of access failure. Occasionally, guide wire or guide catheter induced focal spasm may occur in a tortuous segment. Angiographic visualization of these areas is important as they generally respond to repeat verapamil administration and can be traversed with an angled hydrophilic coated guide wire. A soft-tipped coronary guide wire may also be used to cross these areas (Figure 5).
Sheath-induced spasm is also minimized by the use of sheaths with hydrophilic coating. Kiemeneij has documented that both patient discomfort and the force required to remove a sheath as measured by an automatic pull-back device was significantly less with hydrophilic coated sheaths as opposed to non-coated sheaths.20 Local access bleeding. The most important benefit of transradial procedures is the elimination of access site bleeding complications.1–4 The radial artery puncture site is located over bone and can easily be compressed with minimal pressure. Thus, bleeding from the radial access site can virtually always be prevented. Although manual pressure from an experienced operator is the ideal method to obtain hemostasis, several compression devices have been developed in an attempt to maximize operator and staff efficiency. Local hematomas may occur as a result of improper device application or device failure. It is important to emphasize that compression of the radial artery both proximally and distally to the puncture site must be performed because of retrograde flow from the palmar arch collaterals. Forearm hematoma. Bleeding may occur from a site in the radial artery remote from the access site. The most common cause is perforation of a small side branch by the guide wire in patients receiving a platelet glycoprotein IIb/IIIa inhibitor (Figure 6). Avulsion of a small radial recurrent artery arising from a radial loop is another important cause of this syndrome.21,22 Hydrophilic guidewires preferentially select this small arterial remnant in patients with a radial loop and forceful advancement of the guide catheter can result in avulsion of the vessel. Radial artery perforation has been described in 1% of patients although in our experience the incidence is substantially lower. A low threshold to perform a radial artery arteriogram when any resistance to guide wire or catheter insertion is encountered will help prevent this complication.
Recognition of this bleeding remote from the access site is important as hemostatic pressure must be applied to an area other than the access site. Hemostasis is usually easily accomplished by the application of an Ace bandage to the forearm. A blood pressure sphygmomanometer may also be utilized. The latter is inflated to systolic pressure and then gradually released over a period of one to two hours. Sealing of a perforation with a long sheath is also an option, but this is rarely necessary.22
Compartment syndrome is the most dreaded complication of radial artery hemorrhage. A large hematoma causes hand ischemia due to pressure-induced occlusion of both the radial and ulnar arteries. Fasciotomy with hematoma evacuation must be performed as an emergency procedure to prevent chronic ischemic injury. This complication is rare, occurring only once in our early experience; it should always be preventable.
Access failure. Failure to cannulate the radial artery using a 20 gauge needle and a 0.025 mm straight Terumo guide wire occurs in less than 5% of patients with an experienced operator. The importance of adequate patient sedation and local anesthesia in the prevention of radial artery spasm has previously been emphasized. In addition, meticulous attention to detail is important as the probability of failure increases as the number of unsuccessful attempts to puncture the artery increases. It should be emphasized that the puncture site is proximal to the styloid process of the radius bone. The radial artery distally usually bifurcates and becomes less superficial and attempting to puncture the vessel too distally is a common cause of access failure (Figure 7).
The radial loop is the most common congenital anomaly of the radial artery and may be a cause of access failure. It occurs in 1–2% of patients and may be unilateral or bilateral.21 Wide loops can occasionally be traversed with hydrophilic guidewires and 5 Fr catheters without excessive patient discomfort.23 However, in most cases, it is preferable to consider an alternative access site.
Radial arteries that are smaller than 2 mm in diameter are difficult to access. These are generally seen in smaller women and patients with previous radial procedures. The use of a 5 Fr guide in this situation may be an option. However, complex or difficult procedures cannot be performed through a 5 Fr guide catheter. Miscellaneous complications. Pseudoaneurysm formation may rarely occur at the radial artery access site. This is usually easily managed with thrombin injection and/or mechanical compression. However, surgery may be required. Radial artery avulsion due to intense spasm has been described but this complication should virtually never occur using contemporary techniques. Sterile abscesses rarely occur with the use of hydrophilic coated sheaths.24 Conclusion. The radial artery is an excellent access site for coronary interventions. Although technically more challenging with a definite learning curve, there are significant advantages to this approach. Complications are infrequent and many are preventable with careful technique.
Vascular complications after percutaneous coronary intervention following hemostasis with the Mynx vascular closure device versus the AngioSeal vascular closure device.
Department Cardiology, New York Medical College, Macy Pavilion, Valhalla, NY 10595, USA.
Abstract
We investigated the prevalence of vascular complications after PCI following hemostasis in 190 patients (67% men and 33% women, mean age 64 years) treated with the AngioSeal vascular closure device (St. Jude Medical, Austin, Texas) versus 238 patients (67% men and 33% women, mean age 64 years) treated with the Mynx vascular closure device (AccessClosure, Mountain View, California).
RESULTS:
Death, myocardial infarction or stroke occurred in none of the 190 patients (0%) treated with the AngioSeal versus none of 238 patients (0%) treated with the Mynx. Major vascular complications occurred in 4 of 190 patients (2.1%) treated with the AngioSeal versus 5 of 238 patients (2.1%) treated with the Mynx (p not significant). Major vascular complications in patients treated with the AngioSeal included removal of a malfunctioning device (1.1%), hemorrhage requiring intervention (0.5%) and hemorrhage with a loss of > 3g Hgb (0.5%). The major vascular complications in patients treated with the Mynx included retroperitoneal bleeding requiring surgical intervention (0.8%), pseudoaneurysm with surgical repair (0.8%) and hemorrhage with a loss of > 3g Hgb (0.4%). These complications were not significantly different between the two vascular closure devices (p = 0.77). Minor complications included hematoma > 5 cm (0.5%, n = 1) within the AngioSeal group, as well as procedure failure requiring > 30 minutes of manual compression after device deployment, which occurred in 7 out of 190 patients (3.7%) treated with the AngioSeal versus 22 of 238 patients with the Mynx (9.2%) (p = 0.033).
CONCLUSIONS:
Major vascular complications after PCI following hemostasis with vascular closure devices occurred in 2.1% of 190 patients treated with the AngioSeal vascular closure device versus 2.1% of 238 patients treated with the Mynx vascular closure device (p not significant). The Mynx vascular closure device appears to have a higher rate of device failure.
Incications and complications of invasive diagnostic procedures and percutaneous coronary interventions in the year 2003. Results of the quality control registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK).
The ALKK registry contains about 20% of the invasive and interventional cardiological procedures performed in Germany.
METHODS:
In 2003 a total of 82,282 consecutive diagnostic invasive and 30,689 interventional procedures from 75 hospitals were centrally collected and analyzed.
RESULTS:
The main indication for an invasive diagnostic procedure was coronary artery disease in 92.5% of cases, myocardial disease in 1.6%, impaired left ventricular function in 4.0%, valve disease in 4% and other indications in 1.9%. An acute coronary syndrome was present in 25% of the patients. The rate of severe complications in patients with a lone diagnostic invasive procedure was low (<0.5%). The indication for percutaneous coronary intervention (n=30,689) was stable angina in 44.1%, ST elevation myocardial infarction in 22.3%, non ST elevation myocardial infarction in 14.8%, unstable angina in 10.0%, silent ischemia in 2.2%, prognostic in 5.2% of patients. The majority of interventions were performed directly after the diagnostic procedure (n=23,887=78.6%). The intervention was successful in 94.6% of cases. Stent implantation was performed in 77.2%, with 1 stent in 88.4%, two stents in 7.6% and 3 or more stents in 3.3%. A drug-eluting stent was implanted in 3.6% of the cases. The complication rate after PCI was influenced by the indication for the intervention. The in-hospital mortality in patients with cardiogenic shock was 33%, while in patients with stable angina, silent ischemia and prognostic indication only 0.2% died.
CONCLUSION:
There is an increase of invasive diagnostic and interventional procedures in patients with acute coronary syndromes, with 47% of PCIs performed in these patient. PCIs were performed in 75% of the cases directly after the diagnostic procedure. The rate of stent implantation seems to have reached a plateau at around 80%, while drug-eluting stents were implanted only in a minority of cases. The complication rate is mainly dependent on the clinical presentation of the patients and the indication for PCI.
1Department of Cardiovascular Medicine, 2Department of Pathology, 3Division of Interventional Cardiology, Toho University Faculty of Medicine, Ohta City, Tokyo, Japan
Abstract: Behçet’s disease is a multisystemic vascular inflammatory disease, but concurrent cardiac diseases, such as acute myocardial infarction, are rare. Several complications may arise after coronary intervention for coronary lesions that interfere with treatment, and the incidence of coronary arterial complications due to invasive therapy remains unclear. Further, the long-term outcomes in patients with Behçet’s disease after stenting for acute myocardial infarction have not been described. The present report describes a 35-year-old Japanese man with Behçet’s disease who developed acute myocardial infarction. A coronary aneurysm developed at the stenting site of the left anterior descending coronary artery, along with stenosis in the left anterior descending segment proximal to the site. Although invasive therapy was considered, medication including immunosuppressants was selected because of the high risk of vascular complications after invasive therapy. The coronary artery disease has remained asymptomatic for the 4 years since the patient started medication. This case underscores the importance of considering the incidence of coronary arterial complications and of conservative treatment when possible.
Marso SP, Amin AP, House JA, et al; on behalf of the National Cardiovascular Data Registry. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA. 2010;303(21):2156-2164.
Heart Disease and Stroke Statistics — 2011 Update. American Heart Association, 2011.
Tavris DR, Gallauresi BA, Dey S, Brindis R, Mitchel K. Risk of local adverse events by gender following cardiac catheterization. Pharmacoepidemiol Drug Saf. 2007;16(2):125-131.
Tavris DR, Dey S, Gallauresi B, et al. Risk of local adverse events following cardiac catheterization by hemostasis device use — phase II. J Invasive Cardiol. 2005;17(12):644-650.
An initiative of the American College of Cardiology Foundation, the NCDR, National Cardiovascular Data Registry, is a comprehensive, outcomes-based suite of registries focused on quality improvement. www.ncdr.com.
Applegate RJ, Sacrinty MT, Kutcher MA, et al. Propensity score analysis of vascular complications after diagnostic cardiac catheterization and percutaneous coronary intervention 1998-2003. Catheter Cardiovasc Interv. 2006;67(4):556-562.
Applegate RJ, Sacrinty M, Kutcher MA, et al. Vascular complications with newer generations of Angio-Seal vascular closure devices. J Interv Cardiol. 2006;19(1):67-74.
Applegate RJ, Sacrinty MT, Kutcher MA, et al. Propensity score analysis of vascular complications after diagnostic cardiac catheterization and percutaneous coronary intervention using thrombin hemostatic patch-facilitated manual compression. J Invasive Cardiol. 2007;19(4):164-170.
Sulzbach-Hoke LM, Ratcliffe SJ, Kimmel SE, et al. Predictors of complications following sheath removal with percutaneous coronary intervention. J Cardiovasc Nurs. 2010;25(3):E1-E8.
Legrand V, Doneux P, Martinez C, et al. Femoral access management: comparison between two different vascular closure devices after percutaneous coronary intervention. Acta Cardiol. 2005;60(5):482-488.
Hermiller JB, Simonton C, Hinohara T, et al. The StarClose Vascular Closure System: interventional results from the CLIP study. Catheter Cardiovasc Interv. 2006;68(5):677-683.
Martin JL, Pratsos A, Magargee E, et al. A randomized trial comparing compression, Perclose Proglide and Angio-Seal VIP for arterial closure following percutaneous coronary intervention: the CAP trial. Catheter Cardiovasc Interv. 2008;71(1):1-5.
Deuling JH, Vermeulen RP, Anthonio RA, et al. Closure of the femoral artery after cardiac catheterization: a comparison of Angio-Seal, StarClose, and manual compression. Catheter Cardiovasc Interv. 2008;71(4):518-523.
Wong SC, Bachinsky W, Cambier P, et al; ECLIPSE Trial Investigators. A randomized comparison of a novel bioabsorbable vascular closure device versus manual compression in the achievement of hemostasis after percutaneous femoral procedures: the ECLIPSE (Ensure’s Vascular Closure Device Speeds Hemostasis Trial). JACC Cardiovasc Interv. 2009;2(8):785-793.
Arora N, Matheny ME, Sepke C, Resnic FS. A propensity analysis of the risk of vascular complications after cardiac catheterization procedures with the use of vascular closure devices. Am Heart J. 2007;153(4):606-611.
Castillo-Sang M, Tsang AW, Almaroof B, et al. Femoral artery complications after cardiac catheterization: a study of patient profile. Ann Vasc Surg. 2010;24(3):328-335.
Sanborn TA, Ebrahimi R, Manoukian SV, et al. Impact of femoral vascular closure devices and antithrombotic therapy on access site bleeding in acute coronary syndromes: the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Circ Cardiovasc Interv. 2010;3(1):57-62.
Iqtidar AF, Li D, Mather J, McKay RG. Propensity matched analysis of bleeding and vascular complications associated with vascular closure devices vs standard manual compression following percutaneous coronary intervention. Conn Med. 2011;75(1):5-10.
Marso SP, Amin AP, House JA, et al; National Cardiovascular Data Registry. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA. 2010;303(21):2156-2164.
Ahmed B, Piper WD, Malenka D, et al. Significantly improved vascular complications among women undergoing percutaneous coronary intervention: a report from the Northern New England Percutaneous Coronary Intervention Registry. Circ Cardiovasc Interv. 2009;2(5):423-429.
Trimarchi S, Smith DE, Share D, et al; BMC2 Registry. Retroperitoneal hematoma after percutaneous coronary intervention: prevalence, risk factors, management, outcomes, and predictors of mortality: a report from the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. JACC Cardiovasc Interv. 2010;3(8):845-850.
Vaitkus PT. A meta-analysis of percutaneous vascular closure devices after diagnostic catheterization and percutaneous coronary intervention. J Invasive Cardiol. 2004;16(5):243-246.
Koreny M, Riedmuller E, Nikfardjam M, et al. Arterial puncture closing devices compared with standard manual compression after cardiac catheterization — systematic review and meta-analysis. JAMA. 2004;291(3):350-357.
Nikolsky E, Mehran R, Halkin A, et al. Vascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures: a meta-analysis. J Am Coll Cardiol. 2004;44(6):1200-1209.
Biancari F, D’Andrea V, Di Marco C, et al. Meta-analysis of randomized trials on the efficacy of vascular closure devices after diagnostic angiography and angioplasty. Am Heart J. 2010;159(4):518-531.
Tavris DR, Dey S, Gallauresi B, et al. Risk of local adverse events following cardiac catheterization by hemostasis device use — phase II. J Invasive Cardiol. 2005;17(12): 644-650.
Frequency and Costs of Ischemic and Bleeding Complications After Percutaneous Coronary Interventions: Rationale for New Antithrombotic Therapy
Recent advances in catheter technology and antithrombotic therapy have led to a continuous improvement in outcomes of percutaneous coronary intervention (PCI). These improved outcomes have been associated with broadening of the indications for PCI, with an exponential growth in number of procedures performed, but they have also been paralleled by incremental procedure costs. The estimated costs of PCI currently range from $8,000–$13,000.1 With over 800,000 cases performed each year in the United States (US) alone, this represents over $10 billion annually for the US Healthcare System.2 Roughly half of these costs are incurred by the Center for Medicare and Medicaid Services (CMS, formerly known as the Health Care Financing Administration).3 Total costs of PCI include disposable equipment used during the procedure (balloons, catheters, stents, etc.), cardiac catheterization laboratory overhead and depreciation, nursing and pharmacy costs, laboratory costs and physician services. In addition, factors that have been found to be associated with increased PCI costs include the use of special devices such as atherectomy or vascular closure devices, the use of multiple stents, the use of platelet glycoprotein (GP) IIb/IIIa inhibitors, and the presence of certain patient demographic characteristics including advanced age, gender and other comorbidities.1,4,5 Finally, complications related to the procedure have been identified in several studies as the single most significant contributor to increased costs of PC.5–7
Methods to reduce the cost of PCI include re-use of balloon catheters,8 percutaneous revascularization performed at the same time as diagnostic catheterization,9 reduced anticoagulation, the use of new devices or pharmacological interventions to reduce restenosis and complications, and the use of competitive bidding for cardiac cath lab supplies.10 For example, the evolution of anticoagulation therapy in stented patients from a regime of post-procedural heparin and warfarin to one of thienopyridines and aspirin,11 and the subsequent reduction of length of stay from 4 days in 1995 to 2 days in 2000, have helped keep total procedure costs down.12 In addition, a reduction in complication rates appears to be a key target for cost reduction efforts. In support of this statement, in the economic assessment of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial in high-risk patients, Mark et al. identified bleeding complications, urgent and non-urgent coronary artery bypass graft surgery (CABG), and urgent and non-urgent percutaneous transluminal coronary angioplasty (PTCA) as important correlates of incremental costs.7 Unfortunately, standard aggressive antithrombotic therapy aimed toward a reduction of ischemic complications is often associated with an increase in bleeding complications. In the analysis of the EPIC trial, the benefits of abciximab in decreasing procedure costs through a reduction of ischemic complications were offset by drug acquisition costs and by an increase in bleeding complications.7 Thus, with ischemic complications becoming more rare as a result of improvement in PCI technology and more aggressive antithrombotic therapy, bleeding has become a rather common and costly complication of PCI, with a blood transfusion estimated to add up to $8,000 to the cost of care for the PCI patient.13
Based on these premises, it appears that the next challenge in the care of PCI patients will be to determine how to continue to prevent ischemic complications without increasing the risk of bleeding. This paper examines the frequency of PCI complications in both recent clinical trials and actual practice, discusses the costs of complications, and explores improvements in patient management and particularly changes in anticoagulation therapy that might impact total costs of PCI.
Complication rates in clinical trials
Ischemic complications in clinical trials. Despite advances in PCI technology and adjunctive pharmacotherapy, data from clinical trials indicate that ischemic complications still occur in 5–15% of patients.14–19 Typically, clinical trials define ischemic complications as a combination of death, myocardial infarction (MI; both Q-wave and non-Q wave) and either urgent or any target vessel revascularization (TVR). Different definitions of MI or revascularization can make comparisons across trials difficult. However, comparisons may still be possible through the application of strict meta-analysis methodology. A recent meta-analysis combined data from 6 double-blind PCI trials conducted predominantly in North America between 1993 and 1998.20 A total of 16,546 patients were enrolled in these trials (Table 1). Protocols and case report forms for trials included in the analysis were compared to ensure reasonable consistency of study methods, patient management, data reporting and data structure. Integration of the databases from the trials enabled a direct comparison of key event rates at 7 days, using standard classifications and criteria for severity. The meta-analysis showed that the use of high-dose heparin (175 U/kg) was associated with significantly less frequent clinical ischemic events (8.1%) than lower doses of heparin (100 U/kg; 10.3%). In this same meta-analysis, event rates in patients treated with low-dose heparin (70 U/kg) plus a GP IIb/IIIa inhibitor was 6.5%.20 Although not included in this meta-analysis, it is worth noting that the incidence of death, MI and revascularization in the ESPRIT trial was 9.3% in patients treated with low-dose heparin alone (60 U/kg).21
Bleeding complications in clinical trials. In clinical trials of antiplatelet and anti-thrombotic therapy in PCI, bleeding complications are generally defined using either thrombolysis in myocardial infarction (TIMI)22 or global utilization of streptokinase or tPA outcomes (GUSTO)23 criteria (Table 2). Rates of major bleeding in clinical trials using these criteria are generally less than 2% (Table 3).14–19,21,24,25 However, these restrictive definitions may not capture all clinically significant bleeding. For example, neither the TIMI nor the GUSTO major bleeding definition includes the need for a blood transfusion as part of the criteria. Thus, a broader measure of bleeding using a combination of both major and minor bleeding defined by TIMI or GUSTO criteria appears more likely to be representative of bleeding rates in clinical practice.
In the meta-analysis of contemporary PCI trials, TIMI criteria were used to classify hemorrhagic events, permitting direct comparisons between trials. In the high-dose heparin group, the combination of TIMI major and minor bleeding occurred in 10.5% of patients compared with a rate of 10.7% in the low-dose heparin group, while the bleeding rate was 14.3% in patients receiving a combination of GP IIb/IIIa inhibitors and low-dose heparin.
As shown in Table 3, when both TIMI major and minor bleeding are combined in contemporary PCI trials, bleeding complications average 4–14%, depending on patient characteristics and the drug regime used. In addition, when transfusions are included in the definition, the frequency of bleeding complications increases substantially. For example, in NICE-3, bleeding complications were 10.5% when transfusions were included in the criteria, but only 2% of the patients experienced TIMI major bleeding.26
Notably, the only adjunctive anti-thrombotic agent shown to reduce both ischemic and bleeding complications in PCI is bivalirudin. In the Bivalirudin Angioplasty Trial,27 the risk of bleeding was decreased 62% in the bivalirudin group compared with high-dose heparin. The combined rate of TIMI major and TIMI minor bleeding in bivalirudin patients (n = 2,161) was found to be 4.3% in the meta-analysis of contemporary PCI trials with a corresponding ischemic event rate of 6.6%.20
Complications in practice
Ischemic complications in practice. Rates of ischemic complications in clinical practice are difficult to determine. Although several investigators have published data from multicenter databases, these data tend to be 3–5 years old by the time manuscripts are in print. Since trends in the published literature do show continued reduction in PCI complications over time, the frequency of complications noted in these publications may overestimate the actual rate of complications in clinical practice today. In addition, rates of complications can vary widely across institutions due to differences in practice patterns, definitions, operator skills and resource utilization. For example, in the Society for Cardiac Angiography and Interventions (SCA&I) registry, stent use among laboratories varied from 29–95%.28 Others have found lower complication rates in patients whose procedure was performed by a high-volume operator or in a high-volume institution.29 We identified 6 published reports of PCI complications in clinical practice reporting a variety of ischemic outcomes.1,28–31
Saucedo et al. prospectively collected data on 900 patients undergoing successful elective stent placement in native coronary arteries between January 1994 and December 1995.30 The purpose of this study was to evaluate the incidence and long-term clinical consequences of patients with creatine kinase (CK) myocardial isoenzyme band (CK-MB) elevations after stenting. By design, all patients in this observational study had a successful procedure defined as an increase of > 20% in luminal diameter with final percent diameter stenosis of < 50%, without the occurrence of any major complications (death, Q-wave MI and CABG). Nevertheless, 26.4% of patients had CK-MB elevations 1–5 times the upper limit of normal (ULN) and 8.5% had CK-MB elevations > 5 times ULN. In total, 3.9% of patients required a repeat diagnostic catheterization for recurrent ischemia and 1.2% required urgent target vessel revascularization. In this study, patients requiring the use of GP IIb/IIIa inhibitors were excluded.
The Northern New England group (NNE) collected data on 14,498 patients undergoing PCI between 1994 and 1996.29 In this study, outcomes included the in-hospital occurrence of death; emergency CABG (eCABG) or non-eCABG; or new MI (defined as chest pain, diaphoresis, dyspnea or hypotension associated with the development of new Q-waves or ST-T wave changes and a rise in CK to at least twice normal with a positive CK-MB). Overall, death occurred in 1.2% of patients, CABG in 2.6% (0.8% eCABG and 1.8% non-eCABG), and MI in 2%. Stents were used in 22% of patients enrolled in this registry.
In the National Cardiovascular Network database (NCN), Batchelor et al. reported complications of PCI in 109,708 patients who underwent PCI between 1994 and 1997.31 In this observational study, in-hospital mortality was defined as the occurrence of death after the procedure, MI was defined as the appearance of new Q-waves in 2 contiguous leads on a 12-lead electrocardiogram (ECG) for up to 30 days post-PCI, and repeat revascularization was defined as the need for CABG or additional PCI prior to discharge. In this study, death occurred in 1.3% of patients, Q-wave MI in 1.4% and repeat revascularization in 4.5%. Half of the patients underwent stenting in this study. Notably, this database did not record myocardial enzymes or the use of GP IIb/IIIa inhibitors.
Aronow and colleagues observed outcomes in a cohort of consecutive registry patients undergoing coronary stent placement between 1995 and 1997.32 A total of 373 patients underwent PCI during this time period, with death occurring in 9 patients (2.4%), CABG in 3 (0.8%) and MI in 19 (5.1%, including both QWMI and NQWMI). Repeat diagnostic catheterization was performed in 3.2% of patients and repeat PCI in 0.8%.
The SCA&I registry evaluated outcomes in 16,811 patients undergoing either balloon angioplasty (n = 6,121) or stenting (n = 10,690) between July 1996 and December 1998.28 In this observational analysis, 12.9% of patients received a GP IIb/IIIa inhibitor, 87% of patients enrolled in the database underwent PCI between 1997 and 1998, and 60% of the stent patients were enrolled in 1998. Outcomes reported included in-hospital death (occurring at any time during the hospitalization) and eCABG, defined as CABG occurring immediately after PCI. Death occurred in 0.4% of patients and eCABG in 0.5%.
Finally, Cohen and others recorded in-laboratory complications in 26,421 patients at 70 different centers undergoing PCI in 1998.1 In-laboratory complications were rare, with death occurring in 0.17%, cardiac arrest in 0.32%, stroke in 0.03%, ventricular fibrillation or tachycardia in 0.94%, abrupt closure in 0.71%, and eCABG in 0.53%. Overall, 72% of patients received stents and 20% received GP IIb/IIIa inhibitors.
In addition to published reports of PCI complications, data from unpublished sources can be used to determine outcomes in a more contemporary cohort of patients undergoing PCI.33 The MQ-Profile (MQ-Pro) Database [Cardinal Information Corporation (CIC), Marlborough, Massachusetts] is maintained by CIC, which sells and distributes software to US acute-care hospitals for the collection of detailed clinical and administrative data. Data from 5,373 PCI procedures performed between July 1, 1998 and June 30, 1999 were obtained from the database using International Classification of Diseases 9th Edition (ICD-9) procedure codes for PCI (36.01, 36.02, 36.05). Demographic, clinical and economic data were collected on each patient using a combination of database retrieval and chart review. In this analysis, death was defined as discharge disposition of “deceased”, MI as the presence of ECG changes consistent with MI (new Q-waves or ST-segment changes) or an increase in CK-MB of at least 2 times the testing facility’s ULN. CABG was identified by the presence of ICD-9 procedure code 36.1 and repeat PCI by either code 36.01, 36.02, or 36.05. Failed PCI was defined by the term “failed PTCA” in chart notes (for patients without a previous history of PCI) and recurrent ischemia documented by ECG changes. Death occurred in 2.0% of patients, MI in 3.1%, CABG in 1.3% and repeat PCI in 5.5%. Translated into a combined endpoint similar to those used in clinical trials, the rate of death/MI/revascularization was 11.9%.
Data from these published and unpublished observations of contemporary PCI practice indicate that while in-laboratory ischemic complications are exceedingly rare, in-hospital ischemic complications still occur in a substantial number of patients. Using an approximation of outcomes from these published and unpublished reports, mortality averages 1%, Q-wave MI occurs in 2% of patients, NQWMI in 6%, CABG in 2% and repeat PCI occurs in 3–5% of patients. It is important to underscore that although most deaths following PCI are due to underlying comorbidities (i.e., acute MI, cardiogenic shock, etc.) rather than to the procedure itself, few deaths still occur as a complication of the procedure.34,35 Extrapolated to the estimated PCI population of 800,000 cases per year, then 8,000 people will die and 64,000 will experience an MI. In addition, approximately 16,000 will require CABG and as many as 40,000 will need a repeat PCI before hospital discharge.
From the John P. Robarts Research Institute (M.P., M.E., L.J.K., J.W.F., H.J.M.B) and the Departments of Epidemiology and Biostatistics (M.E.) and Clinical Neurological Sciences (M.E., G.G.F., H.J.M.B.), University of Western Ontario, London, Ontario, Canada.
Correspondence to Dr H.J.M. Barnett, John P. Robarts Research Institute, PO Box 5015, 100 Perth Dr, London, ON N6A 5K8, Canada. E-mail barnett@rri.on.ca
Abstract
Background and Purpose—Carotid endarterectomy (CE) has been shown to be beneficial in patients with symptomatic high-grade (70% to 99%) internal carotid artery stenosis. To achieve this benefit, complications must be kept to a minimum. Complications not associated with the procedure itself, but related to medical conditions, have received little attention.
Methods—Medical complications that occurred within 30 days after CE were recorded in 1415 patients with symptomatic stenosis (30% to 99%) of the internal carotid artery. They were compared with 1433 patients who received medical care alone. All patients were in the North American Symptomatic Carotid Endarterectomy Trial (NASCET).
Results—One hundred fifteen patients (8.1%) had 142 medical complications: 14 (1%) myocardial infarctions, 101 (7.1%) other cardiovascular disorders, 11 (0.8%) respiratory complications, 6 (0.4%) transient confusions, and 10 (0.7%) other complications. Of the 142 complications, 69.7% were of short duration, and only 26.8% prolonged hospitalization. Five patients died: 3 from myocardial infarction and 2 suddenly. Medically treated patients experienced similar complications with one third the frequency. Endarterectomy was ≈1.5 times more likely to trigger medical complications in patients with a history of myocardial infarction, angina, or hypertension (P<0.05).
Conclusions—Perioperative medical complications were observed in slightly fewer than 1 of every 10 patients who underwent CE. The majority of these complications completely resolved. Most complications were cardiovascular and occurred in patients with 1 or more cardiovascular risk factors. In this selected population, the occurrence of perioperative myocardial infarction was uncommon.
The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Endarterectomy Trial showed unequivocal benefit of carotid endarterectomy (CE) in symptomatic patients with high-grade internal carotid artery (ICA) stenosis (70% to 99%).12 The parallel study dealing with symptomatic patients with moderate-grade stenosis (30% to 69%) showed benefits of CE only in a carefully selected group of patients.3 Currently, CE is the most common elective peripheral vascular procedure, which in 1997 was performed in ≈130 000 patients in the United States.4
Despite benefit in the long term, CE may cause complications either by the operation itself or by concomitant medical conditions. The challenge for the future is to reduce the perioperative risk as much as possible. The incidence and type of complications that are directly related to the surgical procedure have been the subject of many reports,5678910 whereas medical complications that are not directly caused by the procedure have received less attention. The aim of the present study is to describe the incidence and type of medical complications that occurred in patients randomized into NASCET and to determine their association with baseline risk factors.
Subjects and Methods
The methods of the NASCET have been described in detail elsewhere.111 Briefly, NASCET was a randomized clinical trial designed to compare the benefit of best medical therapy alone with best medical therapy plus CE in patients with recent transient or nondisabling neurological deficit caused by cerebral or retinal ischemia in the territory of the ICA. Among the exclusions were patients with recent history (6 months) of myocardial infarction, unstable angina pectoris, atrial fibrillation, recent congestive heart failure, and valvular heart disease. For inclusion, the ICA had to have a 30% to 99% stenosis as assessed by selective carotid angiography and to be technically suitable for CE. Baseline evaluations included a detailed medical history and complete physical and neurological examination.
Surgeons were invited to join NASCET if the center had a documented CE stroke and death rate of ≤6% in a minimum of 50 consecutive cases over a 2-year period. Surgery was completed at the earliest opportunity after randomization, and patients underwent a second complete physical and neurological examination 30 days after surgery. All medical and surgical complications that caused transient or permanent disability within the 30-day period were recorded.
Medical complications consisted of myocardial infarction (based on ECG and cardiac enzyme changes), arrhythmia (requiring antiarrhythmic medication), congestive heart failure, angina pectoris, hypertension (diastolic blood pressure >100 mm Hg requiring intravenous medication), hypotension (systolic pressure <90 mm Hg requiring administration of vasopressor agent), sudden death, respiratory problems (pneumonia, atelectasis, pulmonary edema, or exacerbation of chronic obstructive pulmonary disease), renal failure (doubling of preoperative urea and/or creatinine), depression, and confusion (requiring restraint). Complications were considered mild if they were transient and did not prolong hospital stay, moderate if they were transient but caused delay in hospital discharge, and severe if they were associated with permanent disability or death.
In the present study, patients were excluded from the analyses if they had serious complications that were directly attributable to the surgical procedure, such as those due to anesthesia, thrombosis at the operative site, wound hematomas requiring surgical intervention, or deficits from a vagus nerve injury interfering with swallowing. These surgical complications are described in detail elsewhere.12 For comparative purposes, a list of complications that occurred in the medically treated arm of NASCET was compiled for the 32-day period after randomization (ie, the 30-day period plus the average 2 days that lapsed from randomization to CE in the surgical arm). In both the surgical and medical arms, patients were censored at the time of a stroke, since the subsequent medical complications are commonly the result of the stroke.
Cox proportional hazards regression modeling was used to identify baseline factors that increased the risk of perioperative medical complications. Adjusted hazard rates and adjusted hazard ratios were used to summarize the results. The estimated hazard ratio (or relative hazard) is a measure of association that can be interpreted as a relative risk. Hazard ratios with corresponding probability value of <0.05 were considered statistically significant. Adjusted hazard rates were obtained from the regression model by using the mean value for a factor being adjusted.
The modeling strategy consisted of initially fitting a “full” model, which included all factors. A “final” model was determined by eliminating all factors that were not significantly predictive of the medical complications, using a backward selection approach. The “change-in-estimate” strategy was used to determine whether the remaining factors in the final model were independent risk factors. A factor was considered an independent risk factor if the change in hazard ratios between the full and final models was <10%.
Results
A total of 1436 eligible patients were randomized to the surgical arm and 1449 to the medical arm of the NASCET. In the surgical arm, 21 patients were not operated on for various reasons.12 In the medical arm 16 patients crossed over to surgical therapy within 30 days, leaving 1433 patients for analysis. CE was performed in 1415 patients (328 patients with severe stenosis and 1087 with moderate stenosis). Of the 1415, 59 (4.2%) patients had serious surgical complications that excluded them from further analyses, and 115 (8.1%) had medical complications (Table 1⇓). Of the 142 complications, 69.7% were mild, 26.8% were moderate, and 3.5% were severe. Twenty patients had ≥2 complications. No patient had pulmonary embolus, renal failure, or depression requiring medication. Cardiovascular disorders were >4 times as common as all other conditions combined. All 5 severe complications were fatal and were caused by cardiovascular disorders: 3 patients had fatal myocardial infarction, and 2 patients died suddenly. Of the patients with fatal myocardial infarction, 2 patients had massive myocardial infarctions on the day of surgery. In the other patient, CE was prolonged (7 hours) because of intraoperative occlusion of the ICA. Twenty-four hours after CE, the patient had a myocardial infarction followed by cardiac arrest, leaving the patient in a vegetative state. The patient died 2 months later. Two patients died suddenly on days 3 and 6 after CE, and both had a history of previous myocardial infarction. All patients with fatal medical complications were male, and all had multiple cardiovascular risk factors.
North American Symptomatic Carotid Endarterectomy Trial (NASCET). Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453.
European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet. 1991;337:1235–1243.
Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415–1425.
Kozak LJ, Owings MF. Ambulatory and inpatient procedures in the United States, 1995. National Center for Health Statistics. Vital Health Stat 13. 1998;135:1–116.
Hertzer NR. Early complications of carotid endarterectomy: incidence, diagnosis, and management. In: Moore WS, ed. Surgery for Cerebrovascular Disease. Philadelphia, Pa: WB Saunders Co; 1996:625–649.
Young B, Moore WS, Robertson JT, Toole JF, Ernst CB, Cohen SN, Broderick JP, Dempsey RJ, Hosking JD. An analysis of perioperative surgical mortality and morbidity in the Asymptomatic Carotid Atherosclerosis Study. Stroke.1996;27:2216–2224.
Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systemic review. BMJ.1997;315:1571–1517.
North American Symptomatic Carotid Endarterectomy Trial (NASCET) Steering Committee. North American Symptomatic Carotid Endarterectomy Trial: methods, patient characteristics, and progress. Stroke. 1991;22:711–720.
Ferguson GG, Barnett HJM, Eliasziw M, Finan JW, Clagett GP, Barnes R, Barr H, Wallace C, for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Collaborators. North American Symptomatic Carotid Endarterectomy Trial (NASCET): surgical results in 1415 patients. Stroke. In press.
Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA, Feinberg W, Mayberg M. Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;25:1901–1914.
Feinberg WM, Albers GW, Barnett HJ, Biller J, Caplan LR, Carter LP, Hart RG, Hobson RW II, Kronmal RA, Moore WS, Robertson JT, Adams HP, Mayberg M. Guidelines for the management of transient ischemic attacks: from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Circulation. 1994;89:2950–2965.
Wong JH, Findlay JM, Suarez-Almazor ME. Regional performance of carotid endarterectomy: appropriateness, outcomes, and risk factors for complications.Stroke. 1997;28:891–898.
Holton P, Wood JB. The effect of bilateral removal of the carotid bodies and denervation of the carotid sinuses in two human subjects. J Physiol (Lond).1965;181:365–378.
Eliasziw M, Spence JD, Barnett HJM. Carotid endarterectomy does not affect long-term blood pressure: observations from the NASCET. Cerebrovasc Dis.1998;8:20–24.
Solomon RA, Loftus CM, Quest DO, Correll JW. Incidence and etiology if intracerebral hemorrhage following carotid endarterectomy. J Neurosurg.1986;64:29–34.
Hafner DH, Smith RB, King OW, Perdue GD, Stewart MT, Rosenthal D, Jordan WD. Massive intracerebral hemorrhage following carotid endarterectomy. Arch Surg.1987;122:305–307.
Section of Vascular and Endovascular Surgery, Boston University Medical Center, Boston, MA, USA. Alik.Farber@bmc.org
Abstract
OBJECTIVE:
Although dextran has been theorized to diminish the risk of stroke associated with carotid endarterectomy (CEA), variation exists in its use. We evaluated outcomes of dextran use in patients undergoing CEA to clarify its utility.
METHODS:
We studied all primary CEAs performed by 89 surgeons within the Vascular Study Group of New England database (2003-2010). Patients were stratified by intraoperative dextran use. Outcomes included perioperative death, stroke, myocardial infarction (MI), and congestive heart failure (CHF). Group and propensity score matching was performed for risk-adjusted comparisons, and multivariable logistic and gamma regressions were used to examine associations between dextran use and outcomes.
RESULTS:
There were 6641 CEAs performed, with dextran used in 334 procedures (5%). Dextran-treated and untreated patients were similar in age (70 years) and symptomatic status (25%). Clinical differences between the cohorts were eliminated by statistical adjustment. In crude, group-matched, and propensity-matched analyses, the stroke/death rate was similar for the two cohorts (1.2%). Dextran-treated patients were more likely to suffer postoperative MI (crude: 2.4% vs 1.0%; P = .03; group-matched: 2.4% vs 0.6%; P = .01; propensity-matched: 2.4% vs 0.5%; P = .003) and CHF (2.1% vs 0.6%; P = .01; 2.1% vs 0.5%; P = .01; 2.1% vs 0.2%; P < .001). In multivariable analysis of the crude sample, dextran was associated with a higher risk of postoperative MI (odds ratio, 3.52; 95% confidence interval, 1.62-7.64) and CHF (odds ratio, 5.71; 95% confidence interval, 2.35-13.89).
CONCLUSIONS:
Dextran use was not associated with lower perioperative stroke but was associated with higher rates of MI and CHF. Taken together, our findings suggest limited clinical utility for routine use of intraoperative dextran during CEA.
Section of Vascular Surgery Dartmouth-Hitchcock Medical Center, Lebanon, NH 03765, USA. philip.goodney@hitchcock.org
Abstract
OBJECTIVE:
This study investigated risk factors for stroke or death after carotid endarterectomy (CEA) among hospitals of varying type and size participating in a regional quality improvement effort.
METHODS:
We reviewed 2714 patients undergoing 3092 primary CEAs (excluding combined procedures or redo CEA) at 11 hospitals in Northern New England from January 2003 through December 2007. Hospitals varied in size (25 to 615 beds) and comprised community and teaching hospitals. Fifty surgeons reported results to the database. Trained research personnel prospectively collected >70 demographic and clinical variables for each patient. Multivariate logistic regression models were used to generate odds ratios (ORs) and prediction models for the 30-day postoperative stroke or death rate.
RESULTS:
Across 3092 CEAs, there were 38 minor strokes, 14 major strokes, and eight deaths (5 stroke-related) < or =30 days of the index procedure (30-day stroke or death rate, 1.8%). In multivariate analyses, emergency CEA (OR, 7.0; 95% confidence interval [CI], 1.8-26.9; P = .004), contralateral internal carotid artery occlusion (OR, 2.8; 95% CI, 1.3-6.2; P = .009), preoperative ipsilateral cortical stroke (OR, 2.4; 95% CI, 1.1-5.1; P = .02), congestive heart failure (OR, 1.6; 95% CI, 1.1-2.4, P = .03), and age >70 (OR, 1.3; 95% CI, 0.8-2.3; P = .315) were associated with postoperative stroke or death. Preoperative antiplatelet therapy was protective (OR, 0.4; 95% CI, 0.2-0.9; P = .02). Risk of stroke or death varied from <1% in patients with no risk factors to nearly 5% with patients with > or =3 risk factors. Our risk prediction model had excellent correlation with observed results (r = 0.96) and reasonable discriminative ability (area under receiver operating characteristic curve, 0.71). Risks varied from <1% in asymptomatic patients with no risk factors to nearly 4% in patients with contralateral internal carotid artery occlusion (OR, 3.2; 95% CI, 1.3-8.1; P = .01) and age >70 (OR, 2.9; 95% CI, 1.0-4.9, P = .05). Two hospitals performed significantly better than expected. These differences were not attributable to surgeon or hospital volume.
CONCLUSION:
Surgeons can “risk-stratify” preoperative patients by considering the variables (emergency procedure, contralateral internal carotid artery occlusion, preoperative ipsilateral cortical stroke, congestive heart failure, and age), reducing risk with antiplatelet agents, and informing patients more precisely about their risk of stroke or death after CEA. Risk prediction models can also be used to compare risk-adjusted outcomes between centers, identify best practices, and hopefully, improve overall results.
The patient with sepsis has severely altered physiology in a number of ways, which can influence cardiac function. Firstly, there is a
Loss of intravascular volume due to excessive third space loss that results in a decrease in preload. Systemic vascular resistance is decreased which results in a fall in afterload. In addition,
end diastolic volumes often increase and
ejection fraction falls. However, many of these changes are overcome by an
increase in heart rate that may result in an increase in cardiac output. However, it should be remembered that even in the presence of high cardiac outputs it is usually always possible to demonstrate
ventricular dysfunction in patients with sepsis. Echocardiographic studies consistently confirm that there is decreased left ventricular systolic function in humans with sepsis.
In addition, there have been many studies in animals and a few in humans which have confirmed the presence of
diastolic dysfunction – particularly in those patients that go on to die from sepsis.
In the presence of adequate fluid resuscitation there is an increase in end diastolic volume and this is probably a normal response to a decrease in contractility. However, in the non-survivors of sepsis there is a normal or low end diastolic volume that is the result of a decrease in ventricular diastolic compliance. Thus, there is a decreased end diastolic volume at the same filling pressure.
During sepsis, a
decrease in contractility results in a shift to the right of the end-systolic pressure / volume curve and if this is not compensated for results in a
a decrease in stroke volume and cardiac output.
When patients with sepsis are appropriately fluid resuscitated there is an
increase in end diastolic pressure that increases stroke volume. In addition, the
decrease in afterload will also increase stroke volume and will prevent a decrease in ejection fraction.
Alas, because there is a decrease in systolic contractility it would be expected that there would also be a decrease in diastolic stiffness which would allow cardiac output to be maintained despite the relatively low filling pressures. However, if this diastolic compliance change does not occur (as in the nonsurvivors of sepsis) then it is apparent that the ability of the ventricle to generate a stroke volume is impaired at both ends of the curve.
The cause of the altered cardiac function in sepsis remains unknown although there are many theoretical explanations. Clearly, one of the most important mechanisms which can be readily corrected is hypovolaemia.
Myocardial oedema may contribute to a decrease in contractility.
Increased circulating catecholamines can result in a decrease in diastolic compliance, particularly important since these agents are often used to improve myocardial contractility.
Increased intrathoracic pressure caused by positive pressure ventilation can also result in decreased diastolic compliance. In addition, many of the
mediators of the inflammatory response, including products of activated endothelial cells and polymorphonuclear leucocytes (e.g. nitric oxide, tumour necrosis factor and interleukins 1 and 2) have all been postulated as negative inotropes and negative lusitropes.
Another, as yet, unidentified agent which is believed to be released from the splanchnic bed –
myocardial depressant factor – is postulated to play a role.
Treatments aimed at correcting the effects of these various inflammatory mediators may be eventually found but until these approaches have been proven to be beneficial the septic patient will continue to be managed according to the physiological principles outlined by Starling.
From the Department of Medicine (M.W.M.), Division of Cardiology, Pulmonary Diseases and Vascular Medicine and the Institute of Molecular Cardiovascular Research (IMCAR) at the University Hospital (C.W.), RWTH Aachen University, Aachen, Germany.
Correspondence to Marc W. Merx, MD, Medizinische Klinik I, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mailmmerx@ukaachen.de), or Christian Weber, MD, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mail cweber@ukaachen.de).
Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsishave been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur.
A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include
cytokines,
prostanoids, and
nitric oxide, among others.
Endothelial activation and
induction of the coagulatory system also contribute to the pathophysiology in sepsis.
Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.
Sepsis, defined by consensus conference as “the systemic inflammatory response syndrome (SIRS) that occurs during infection,”1 is generally viewed as a disease aggravated by the inappropriate immune response encountered in the affected individual (for review, see Hotchkiss and Karl2 and Riedemann et al,3). The Table gives the current criteria for the establishment of the diagnosis of systemic inflammatory response syndrome, sepsis, and septic shock.1,4 Morbidity and mortality are high, resulting in sepsis and septic shock being the 10th most common cause of death in the United States.5 The incidence of sepsis and sepsis-related deaths appears to be increasing by 1.5% per year.6 In a recent study,6 the total national hospital cost invoked by severe sepsis in the United States was estimated at approximately $16.7 billion on the basis of an estimated severe sepsis rate of 751 000 cases per year with 215 000 associated deaths annually. A recent study from Britain documented a 46% in-hospital mortality rate for patients presenting with severe sepsis on admission to the intensive care unit.7
Current Criteria for Establishment of the Diagnosis of SIRS, Sepsis, and Septic Shock1,4
As an important organ system frequently affected by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. In 1951, Waisbren was the first to describe cardiovascular dysfunction due to sepsis.8 He recognized a hyperdynamic state with full bounding pulses, flushing, fever, oliguria, and hypotension. In addition, he described a second, smaller patient group who presented clammy, pale, and hypotensive with low volume pulses and who appeared more severely ill. With hindsight, the latter group might well have been volume underresuscitated, and indeed, timely and adequate volume therapy has been demonstrated to be one of the most effective supportive measures in sepsis therapy.9
Under conditions of adequate volume resuscitation, the profoundly reduced systemic vascular resistance typically encountered in sepsis10 leads to a concomitant elevation in cardiac index that obscures the myocardial dysfunction that also occurs. However, as early as the mid-1980s, significant reductions in both stroke volume and ejection fraction in septic patients were observed despite normal total cardiac output.11 Importantly, the presence of cardiovascular dysfunction in sepsis is associated with a significantly increased mortality rate of 70% to 90% compared with 20% in septic patients without cardiovascular impairment.12 Thus, myocardial dysfunction in sepsis has been the focus of intense research activity. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear.
The purpose of the present review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. This review is not intended to be all inclusive.
Characteristics of Myocardial Dysfunction in Sepsis
Using portable radionuclide cineangiography, Calvin et al13 were the first to demonstrate myocardial dysfunction in adequately volume-resuscitated septic patients with decreased ejection fraction and increased end-diastolic volume index. Adding pulmonary artery catheters to serial radionuclide cineangiography, Parker and colleagues11 extended these observations with the 2 major findings that (1) survivors of septic shock were characterized by increased end-diastolic volume index and decreased ejection fraction, whereas nonsurvivors typically maintained normal cardiac volumes, and (2) these acute changes in end-diastolic volume index and ejection fraction, although sustained for several days, were reversible. More recently, echocardiographic studies have demonstrated impaired left ventricular systolic and diastolic function in septic patients.14–16 These human studies, in conjunction with experimental studies ranging from the cellular level17 to isolated heart studies18,19 and to in vivo animal models,20–22 have clearly established decreased contractility and impaired myocardial compliance as major factors that cause myocardial dysfunction in sepsis.
Notwithstanding the functional and structural differences between the left and right ventricle, similar functional alterations, as discussed above, have been observed for the right ventricle, which suggests that right ventricular dysfunction in sepsis closely parallels left ventricular dysfunction.23–26 However, the relative contribution of the right ventricle to septic cardiomyopathy remains unknown.
Myocardial dysfunction in sepsis has also been analyzed with respect to its prognostic value. Parker et al,27 reviewing septic patients on initial presentation and at 24 hours to determine prognostic indicators, found a heart rate of <106 bpm to be the only cardiac parameter on presentation that predicted a favorable outcome. At 24 hours after presentation, a systemic vascular resistance index >1529 dyne · s−1 · cm−5 · m−2, a heart rate <95 bpm or a reduction in heart rate >18 bpm, and a cardiac index >0.5 L · min−1 · m−2 suggested survival.27 In a prospective study, Rhodes et al28 demonstrated the feasibility of a dobutamine stress test for outcome stratification, with nonsurvivors being characterized by an attenuated inotropic response. The well-established biomarkers in myocardial ischemia and heart failure, cardiac troponin I and T, as well as B-type natriuretic peptide, have also been evaluated with regard to sepsis-associated myocardial dysfunction. Although B-type natriuretic peptide studies have delivered conflicting results in septic patients (for review, see Maeder et al29), several small studies have reported a relationship between elevated cardiac troponin T and I and left ventricular dysfunction in sepsis, as assessed by echocardiographic ejection fraction30–33 or pulmonary artery catheter–derived left ventricular stroke work index.34 Cardiac troponin levels also correlated with the duration of hypotension35 and the intensity of vasopressor therapy.34In addition, increased sepsis severity, measured by global scores such as the Simplified Acute Physiology Score II (SAPS II) or the Acute Physiology And Chronic Health Evaluation II score (APACHE II), was associated with increased cardiac troponin levels,31,33 as was poor short-term prognosis.32,33,35,36 Despite the heterogeneity of study populations and type of troponin studied, the mentioned studies were univocal in concluding that elevated troponin levels in septic patients reflect higher disease severity, myocardial dysfunction, and worse prognosis. In a recent meta-analysis of 23 observational studies, Lim et al37 found cardiac troponin levels to be increased in a large percentage of critically ill patients. Furthermore, in a subset of studies that permitted adjusted analysis and comprised 1706 patients, this troponin elevation was associated with an increased risk of death (odds ratio, 2.5; 95% CI, 1.9 to 3.4, P<0.001)37; however, the underlying mechanisms clearly require further research.
Thus, it appears reasonable to recommend inclusion of cardiac troponins in the monitoring of patients with severe sepsis and septic shock to facilitate prognostic stratification and to increase alertness to the presence of cardiac dysfunction in individual patients. However, it remains to be shown whether risk stratification based on cardiac troponins can identify patients in whom aggressive therapeutic regimens might reap the greatest benefit and so translate into a survival benefit.
Mechanisms Underlying Myocardial Dysfunction in Sepsis
Cardiac depression during sepsis is probably multifactorial (Figure). Nevertheless, it is important to identify individual contributing factors and mechanisms to generate worthwhile therapeutic targets. As a consequence, a vast array of mechanisms, pathways, and disruptions in cellular homeostasis have been examined in septic myocardium.
View larger version:
Synopsis of potential underlying mechanisms in septic myocardial dysfunction. MDS indicates myocardial depressant substance.
Global Ischemia
An early theory of myocardial depression in sepsis was based on the hypothesis of global myocardial ischemia; however, septic patients have been shown to have high coronary blood flow and diminished coronary artery–coronary sinus oxygen difference.38 As in the peripheral circulation, these alterations can be attributed to disturbed flow autoregulation or disturbed oxygen utilization.39,40 Coronary sinus blood studies in patients with septic shock have also demonstrated complex metabolic alterations in septic myocardium, including increased lactate extraction, decreased free fatty acid extraction, and decreased glucose uptake.41 Furthermore, several magnetic resonance studies in animal models of sepsis have demonstrated the presence of normal high-energy phosphate levels in the myocardium.42,43 It has also been proposed that myocardial dysfunction in sepsis may reflect hibernating myocardium.44 To reach this conclusion, Levy et al44 studied a murine cecal ligation and double-puncture model and observed diminished cardiac performance, increased myocardial glucose uptake, and deposits of glycogen in a setting of preserved arterial oxygen tension and myocardial perfusion. Although all of the above-mentioned findings reflect important alterations in coronary flow and myocardial metabolism, mirroring effects observed in peripheral circulation during sepsis, there is no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis. However, in septic patients with coexistent and possibly undiagnosed coronary artery disease (CAD), regional myocardial ischemia or infarction secondary to CAD may certainly occur. The manifestation of myocardial ischemia due to CAD might even be facilitated by the volatile hemodynamics in sepsis, as well as by the generalized microvascular dysfunction so frequently observed in sepsis.45 Additional CAD-aggravating factors encountered in sepsis encompass generalized inflammation and the activated coagulatory system. Furthermore, the endothelium plays a prominent role in sepsis (see below), but little is known of the impact of preexisting, CAD-associated endothelial dysfunction in this context. In a postmortem study of 21 fatal cases of septic shock, previously undiagnosed myocardial ischemia at least contributed to death in 7 of the 21 cases (all 21 patients were males, with a mean age of 60.4 years).46 It certainly appears prudent to remain wary of CAD complications while treating sepsis, especially in patients with identifiable risk factors and in view of the ever-increasing mean age of intensive care unit patients and including septic patients.
Myocardial Depressant Substance
A circulating myocardial depressant factor in septic shock was first proposed more than 50 years ago.47 Parrillo et al48 quantitatively linked the clinical degree of septic myocardial dysfunction with the effect the serum, taken from respective patients, had on rat cardiac myocytes, with clinical severity correlating well with the decrease in extent and velocity of myocyte shortening. These effects were not seen when serum from convalescent patients whose cardiac function had returned to normal was applied or when serum was obtained from other critically ill, nonseptic patients.48 In extension of these findings, ultrafiltrates from patients with severe sepsis and simultaneously reduced left ventricular stroke work index (<30 g · m−1 · m−2) displayed cardiotoxic effects and contained significantly increased concentrations of interleukin (IL)-1, IL-8, and C3a.49Recently, Mink et al50 demonstrated that lysozyme c, a bacteriolytic agent believed to originate mainly from disintegrating neutrophilic granulocytes and monocytes, mediates cardiodepressive effects during Escherichia coli sepsis and, importantly, that competitive inhibition of lysozyme c can prevent myocardial depression in the respective experimental sepsis model. Additional potential candidates for myocardial depressant substance include other cytokines, prostanoids, and nitric oxide (NO). Some of these will be discussed below.
Cytokines
Infusion of lipopolysaccharide (LPS, an obligatory component of Gram-negative bacterial cell walls) into both animals and humans51 partially mimics the hemodynamic effects of septic shock.51,52 However, only a minority of patients with septic shock have detectable LPS levels, and the prolonged time course of septic myocardial dysfunction and the chemical characteristics of LPS are not consistent with LPS representing the sole myocardial depressant substance.48,53 Tumor necrosis factor-α (TNF-α) is an important early mediator of endotoxin-induced shock.54 TNF-α is derived from activated macrophages, but recent studies have shown that TNF-α is also secreted by cardiac myocytes in response to sepsis.55 Although application of anti-TNF-α antibodies improved left ventricular function in patients with septic shock,56 subsequent studies using monoclonal antibodies directed against TNF-α or soluble TNF-α receptors failed to improve survival in septic patients.57–59 IL-1 is synthesized by monocytes, macrophages, and neutrophils in response to TNF-α and plays a crucial role in the systemic immune response. IL-1 depresses cardiac contractility by stimulating NO synthase (NOS).60 Transcription of IL-1 is followed by delayed transcription of IL-1 receptor antagonist (IL-1-ra), which functions as an endogenous inhibitor of IL-1. Recombinant IL-1-ra was evaluated in phase III clinical trials, which showed a tendency toward improved survival61 and increased survival time in a retrospective analysis of the patient subgroup with the most severe sepsis62; however, to date, this initially promising therapy has failed to deliver a statistically significant survival benefit. IL-6, another proinflammatory cytokine, has also been implicated in the pathogenesis of sepsis and is considered a more consistent predictor of sepsis than TNF-α because of its prolonged elevation in the circulation.63 Although cytokines may very well play a key role in the early decrease in contractility, they cannot explain the prolonged duration of myocardial dysfunction in sepsis, unless they result in the induction or release of additional factors that in turn alter myocardial function, such as prostanoids or NO.64,65
Prostanoids
Prostanoids are produced by the cyclooxygenase enzyme from arachidonic acid. The expression of cyclooxygenase enzyme-2 is induced, among other stimuli, by LPS and cytokines (cyclooxygenase enzyme-1 is expressed constitutively).66 Elevated levels of prostanoids such as thromboxane and prostacyclin, which have the potential to alter coronary autoregulation, coronary endothelial function, and intracoronary leukocyte activation, have been demonstrated in septic patients.67 Early animal studies with cyclooxygenase inhibitors such as indomethacin yielded very promising results.68,69Along with other positive results, these led to an important clinical study involving 455 septic patients who were randomized to receive intravenous ibuprofen or placebo.70Unfortunately, that study did not demonstrate improved survival for the treatment arm. Similarly, a more recent, smaller study on the effects of lornoxicam failed to provide evidence for a survival benefit through cyclooxygenase inhibition in sepsis.71 Animal studies aimed at elucidating possible benefits of isotype-selective cyclooxygenase inhibition have so far produced conflicting results.72,73
Endothelin-1
Endothelin-1 (ET-1; for an in-depth review of endothelin in sepsis, see Gupta et al74) upregulation has been demonstrated within 6 hours of LPS-induced septic shock.75Cardiac overexpression of ET-1 triggers an increase in inflammatory cytokines (among others, TNF-α, IL-1, and IL-6), interstitial inflammatory infiltration, and an inflammatory cardiomyopathy that results in heart failure and death.76 The involvement of ET-1 in septic myocardial dysfunction is supported by the observation that tezosentan, a dual endothelin-A and endothelin-B receptor antagonist, improved cardiac index, stroke volume index, and left ventricular stroke work index in endotoxemic shock.77 However, higher doses of tezosentan exhibited cardiotoxic effects and led to increased mortality.77Although ET-1 has been demonstrated to be of pathophysiological importance in a wide array of cardiac diseases through autocrine, endocrine, or paracrine effects, its biosynthesis, receptor-mediated signaling, and functional consequences in septic myocardial dysfunction warrant further investigation to assess the therapeutic potential of ET-1 receptor antagonists.
Nitric Oxide
NO exerts a plethora of biological effects in the cardiovascular system.78 It has been shown to modulate cardiac function under physiological and a multitude of pathophysiological conditions. In healthy volunteers, low-dose NO increases LV function, whereas inhibition of endogenous NO release by intravenous infusion of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine reduced the stroke volume index.79 Higher doses of NO have been shown to induce contractile dysfunction by depressing myocardial energy generation.80 The absence of the important NO scavenger myoglobin (Mb) in Mb knockout mice results in impaired cardiac function that is partially reversible by NOS inhibition.81 Endogenous NO contributes to hibernation in response to myocardial ischemia by reducing oxygen consumption and preserving calcium sensitivity and contractile function.82 NO also represents a potent modulator of myocardial ischemia/reperfusion injury. However, as in sepsis-related NO research, the reported effects of NO on ischemia/reperfusion injury are inconsistent owing to a multitude of confounding experimental factors.83
Sepsis leads to the expression of inducible NOS (iNOS) in the myocardium,84,85 followed by high-level NO production, which in turn importantly contributes to myocardial dysfunction, in part through the generation of cytotoxic peroxynitrite, a product of NO and superoxide (for an excellent review, see Pacher et al86). In iNOS-deficient mice, cardiac function is preserved after endotoxin challenge.87 Nonspecific NOS inhibition restores cardiac output and stroke volume after LPS injection.88 Strikingly, in septic patients, infusion of methylene blue, a nonspecific NOS inhibitor, improves mean arterial pressure, stroke volume, and left ventricular stroke work and decreases the requirement for inotropic support but, unfortunately, does not alter outcome.89 An interesting study comparing the inhibition of NO superoxide and peroxynitrite in cytokine-induced myocardial contractile failure found peroxynitrite to indeed be the most promising therapeutic target.90 It has also been proposed that the constitutively expressed mitochondrial isoform of NOS (mtNOS), the expression of which can be augmented by induction, controls rates of oxidative phosphorylation by inhibiting various steps of the respiratory chain.91 Although this hypothesis would provide a plausible explanation for the reduced coronary oxygen extraction observed during sepsis (see above), the effects of sepsis on expression of mtNOS and NO generation remain to be explored. Furthermore, the constitutively expressed endothelial NOS (eNOS), previously neglected in the context of sepsis, has been shown to be an important regulator of iNOS expression, resulting in a more stable hemodynamic status in eNOS-deficient mice after endotoxemia.92 Very recently, a functional NOS in red blood cells (rbcNOS) was identified that regulates deformability of erythrocyte membranes and inhibits activation of platelets.93 With both effect targets thus far demonstrated for rbcNOS lying at the core of microvascular dysfunction in sepsis, this discovery opens a whole new window to NO-related sepsis research. Given the existence of different NOS isoforms and their various modulating interactions, dose-dependent NO effects, and the precise balance of NO, superoxide, and thus peroxynitrite generated in subcellular compartments, further advances in our understanding of the complex NO biology and its derived reactive nitrogen species hold the promise of revealing new, more specific and effective therapeutic targets.
Adhesion Molecules
Surface-expression upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 has been demonstrated in murine coronary endothelium and cardiomyocytes after LPS and TNF-α stimulation.94 After cecal ligation and double puncture, myocardial intercellular adhesion molecule-1 expression increases in rats.95Vascular cell adhesion molecule-1 blockade with antibodies has been shown to prevent myocardial dysfunction and decrease myocardial neutrophil accumulation,94,96 whereas both knockout and antibody blockade of intercellular adhesion molecule-1 ameliorate myocardial dysfunction in endotoxemia without affecting neutrophil accumulation.94 In addition, neutrophil depletion does not protect against septic cardiomyopathy, which suggests that the cardiotoxic potential of neutrophils infiltrating the myocardium is of lesser importance in this context.94 Other aspects of adhesion molecules are discussed in conjunction with possible statin effects below.
The e-Reader is advised to consider the following expansion on the subject matter carrying the discussion to additional related clinical issues:
Therapeutic Approaches: The Present and the Future
A detailed discussion of therapeutic options in septic patients would clearly be beyond the scope of this review, and readers are kindly referred to the multiple excellent reviews published on the subject (eg, Hotchkiss and Karl,2 Annane et al,4 and Dellinger et al97). Although a number of preventive measures, such as prophylactic antibiotics, maintenance of normoglycemia, selective digestive tract decontamination, vaccines, and intravenous immunoglobulin, have shown benefit in distinct patient populations, preventive strategies with a broader aim remain elusive. Once sepsis is manifest (see the Table for criteria), prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. Supportive therapy encompasses early and goal-directed fluid resuscitation,9 vasopressor and inotropic therapy, red blood cell transfusion, mechanical ventilation, and renal support when indicated. It is very likely beneficial to monitor cardiac performance in these patients. A wide array of techniques are available for this purpose, ranging from echocardiography to pulmonary catheters, thermodilution techniques, and pulse pressure analysis.98 Because none of these techniques have demonstrated superiority, physicians should use the method with which they are most familiar. Whichever method is chosen, it should be applied frequently to tailor supportive therapy to the individual patient and to achieve the “gold standard” of early goal-directed therapy. In recent years, several attempts have been made to therapeutically address myocardial dysfunction in sepsis. Although the combination of norepinephrine as vasopressor and dobutamine as inotropic agent is probably the most frequently applied in septic shock, there is currently no evidence to recommend one catecholamine over the other.97 In human endotoxemia, epinephrine has been demonstrated to inhibit proinflammatory pathways and coagulation activation, as well as to augment antiinflammatory pathways,99,100 whereas no immunomodulatory or coagulant effects could be demonstrated for dobutamine in a similar setting.101 Isoproterenol has recently been applied successfully in a small group of patients with septic shock, no known history of CAD, and inappropriate mixed venous oxygen concentration despite correction of hypoxemia and anemia.102 In a cecal ligation and double-puncture model of sepsis, the β-blocker esmolol given continuously after sepsis induction improved myocardial oxygen utilization and attenuated myocardial dysfunction,103 which suggests that therapeutic strategies proven in ischemic heart failure might also hold promise in septic cardiomyopathy. However, the optimal mode of β-receptor stimulation (or indeed inhibition) to limit myocardial dysfunction remains a wide-open field for inspired investigation.
Given the generally accepted view of sepsis as a disease largely propelled by an inappropriate immune response, numerous basic research and clinical trials have been undertaken to curb the lethal toll of sepsis through modulation of this uncontrolled immune response.2,3 To date, activated protein C104 and low-dose hydrocortisone105 have emerged as the only inflammation-modulating substances that have been confirmed to be of benefit in patients with severe sepsis and septic shock. Over the past years, increasing evidence has accumulated that suggests that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or statins, have therapeutic benefits independent of cholesterol lowering, termed “pleiotropic” effects. These have added a wide scope of potential targets for statin therapy that range from decreasing renal function loss106 and lowering mortality in patients with diastolic heart failure107 to prevention and treatment of stroke,108 to name just a few. These pleiotropic effects include antiinflammatory and antioxidative properties, improvement of endothelial function, and increased NO bioavailability and thus might contribute to the benefit observed with statin therapy. Notably, these important immunomodulatory effects of statins have been demonstrated to be independent of lipid lowering109 and appear to be mediated via interference with the synthesis of mevalonate metabolites (nonsteroidal isoprenoid products). Blockade of the mevalonate pathway has been shown to suppress T-cell responses,110 reduce expression of class II major histocompatibility complexes on antigen presenting cells,109 and inhibit chemokine synthesis in peripheral blood mononuclear cells.111 Furthermore, CD11b integrin expression and CD11b-dependent adhesion of monocytes have been found to be attenuated by the initiation of statin treatment in hypercholesterolemic patients.112 In this context, Yoshida et al113 have reported that statins reduce the expression of both monocytic and endothelial adhesion molecules, eg, the integrin leukocyte function-associated antigen-1 (LFA-1), via an inhibition of Rho GTPases, in particular their membrane anchoring by geranylation. In addition, mechanisms for antiinflammatory actions of statins have been revealed that are not related to the isoprenoid metabolism. For instance, Weitz-Schmidt et al114 have identified that some statins act as direct antagonists of LFA-1 owing to their capacity to bind to the regulatory site in the LFA-1 i-domain. In addition to these multifaceted antiinflammatory effects, statins may interfere with activation of the coagulation cascade, as illustrated by the suppression of LPS-induced monocyte tissue factor in vitro.115 Beyond their immunomodulatory functions, statins have been shown to exert direct antichlamydial effects during pulmonary infection with Chlamydia pneumoniae in mice,116 and a recent report suggests the benefit of statins may also extend to viral pathogens.117
Given the strong impact of statins on inflammation, statins might represent a welcome enforcement in the battle against severe infectious diseases such as sepsis. Consequently, several investigators have evaluated the role of statins in the prevention and treatment of sepsis. In a retrospective analysis, Liappis et al118 demonstrated a reduced overall and attributable mortality in patients with bacteremia who were treated concomitantly with statins. Pretreatment with simvastatin has been shown to profoundly improve survival in a polymicrobial murine model of sepsis by preservation of cardiovascular function and inhibition of inflammatory alterations.19 Encouraged by these findings, the same model was used to successfully treat sepsis in a clinically feasible fashion, ie, treatment was initiated several hours after the onset of sepsis. With different statins (atorvastatin, pravastatin, and simvastatin) being effective, the therapeutic potential of statins in sepsis appears to be a class effect.22 Recently, Steiner et al119observed that pretreatment with simvastatin can suppress the inflammatory response induced by LPS in healthy human volunteers. Furthermore, in a prospective observational cohort study in patients with acute bacterial infections performed by Almog et al,120previous treatment with statins was associated with a considerably reduced rate of severe sepsis and intensive care unit admissions. A total of 361 patients were enrolled in that study, and 82 of these patients had been treated with statins for at least 4 weeks before their admission. Severe sepsis developed in 19% of patients in the no-statin group compared with only 2.4% in patients who were taking statins. The intensive care unit admission rates were 12.2% for the no-statin group and 3.7% for the statin group. Because of the number of patients enrolled, the study was not powered to detect differences in mortality, although the large effect on sepsis rate and intensive care unit admission were at least suggestive. As the most recent development in this field, Hackam et al121 have produced an impressive observational study by initial evaluation of 141 487 cardiovascular patients, which resulted in a well-paired and homogenous study cohort of 69 168 patients after propensity-based matching. Drawing from this solid base, Hackam and coauthors were able to support the conclusion that statin therapy is associated with a considerably decreased rate of sepsis (hazard ratio, 0.81; 95% CI, 0.72 to 0.90), severe sepsis (hazard ratio, 0.83; 95% CI, 0.70 to 0.97), and fatal sepsis (hazard ratio, 0.75; 95% CI, 0.61 to 0.93). This protective effect prevailed at both high and low statin doses and for several clinically important subpopulations, such as diabetic and heart failure patients.
As has been suggested previously,122 statins might provide cumulative benefit by reducing mortality from cardiovascular and infectious diseases such as sepsis. However, statins may have detrimental effects in distinct subsets of patients. Therefore, caution should prevail, and the use of statins in patients with sepsis must be accompanied by meticulous monitoring of unexpected side effects and well-designed randomized, controlled clinical trials.
Beyond an apparent rationale for randomized trials on statins in sepsis, it is notable that the results with other immunomodulatory approaches in sepsis have yielded rather limited success. For instance, use of the anti-TNF antibody F(ab′)2 fragment afelimomab led to a significant but rather modest reduction in risk of death and to improved organ-failure scores in patients with severe sepsis and elevated IL-6 levels.123 Moreover, a selective inhibitor of group IIA secretory phospholipase A2 failed to improve clinical outcome for patients with severe sepsis, with a negative trend most pronounced among patients with cardiovascular failure.124 Hence, because none of the available strategies proven to be effective in sepsis are designed specifically to target myocardial dysfunction, one might conclude that strategies that preferentially address cardiac morbidity in sepsis may be a promising area for investigation. For instance, lipoteichoic acid, a major virulence factor in Gram-positive sepsis, causes cardiac depression by activating myocardial TNF-α synthesis via CD14 and induces coronary vascular disturbances by activating thromboxane 2 synthesis. It thus contributes to cardiac depression and may therefore be a worthwhile and cardiac-specific target.125 The implications of intensified efforts in the search for successful novel approaches to the treatment of myocardial dysfunction in sepsis may be considerable with regard to improved patient care that results in reduced mortality. This is of major significance in view of the substantial economic consequences of increasing sepsis morbidity in an aging population.
REFERENCES
in Circulation.2007; 116: 793-802 doi: 10.1161/CIRCULATIONAHA.106.678359
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992; 101: 1644–1655.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29: 1303–1310.
Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003; 31: 2332–2338.
Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella: a clinical and therapeutic study. AMA Arch Intern Med. 1951; 88: 467–488.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med.2001; 345: 1368–1377.
Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984; 100: 483–490.
Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990; 113:227–242.
Calvin JE, Driedger AA, Sibbald WJ. An assessment of myocardial function in human sepsis utilizing ECG gated cardiac scintigraphy. Chest. 1981; 80: 579–586.
Munt B, Jue J, Gin K, Fenwick J, Tweeddale M. Diastolic filling in human severe sepsis: an echocardiographic study. Crit Care Med. 1998; 26: 1829–1833.
Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med. 1997; 23: 553–560.
Ren J, Ren BH, Sharma AC. Sepsis-induced depressed contractile function of isolated ventricular myocytes is due to altered calcium transient properties. Shock.2002; 18: 285–288.
Natanson C, Fink MP, Ballantyne HK, Mac Vittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest.1986; 78: 259–270.
Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005; 112: 117–124.
Vincent JL, Thirion M, Brimioulle S, Lejeune P, Kahn RJ. Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter. Intensive Care Med. 1986; 12: 33–38.
Dhainaut JF, Brunet F, Monsaillier JF, Villemant D, Devaux JY, Konno M, De Gournay JM, Armaganidis A, Iotti G, Huyghebaert MF. Bedside evaluation of right ventricular performance using a rapid computerized thermodilution method. Crit Care Med. 1987; 15: 148–152.
Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest. 1990; 97: 126–131.
Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med. 1987; 15: 923–929.
Rhodes A, Lamb FJ, Malagon I, Newman PJ, Grounds RM, Bennett ED. A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock. Crit Care Med. 1999; 27: 2361–2366.
Maeder M, Fehr T, Rickli H, Ammann P. Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides. Chest. 2006; 129: 1349–1366.
ver Elst KM, Spapen HD, Nguyen DN, Garbar C, Huyghens LP, Gorus FK. Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock. Clin Chem. 2000; 46: 650–657.
Mehta NJ, Khan IA, Gupta V, Jani K, Gowda RM, Smith PR. Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock. Int J Cardiol.2004; 95: 13–17.
Arlati S, Brenna S, Prencipe L, Marocchi A, Casella GP, Lanzani M, Gandini C. Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study. Intensive Care Med. 2000; 26: 31–37.
Spies C, Haude V, Fitzner R, Schroder K, Overbeck M, Runkel N, Schaffartzik W. Serum cardiac troponin T as a prognostic marker in early sepsis. Chest. 1998;113: 1055–1063.
Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR. Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol.1995; 79: 479–486.
Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts WC, Quezado ZM, Scholz TD, Cunnion RE, Hoffman WD, Bacher J, Yatsiv I, Danner RL, Banks SM, Ferrans VJ, Balaban RS, Natanson C. Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol Heart Circ Physiol. 1994; 266: H757–H768.
Van Lambalgen AA, van Kraats AA, Mulder MF, Teerlink T, van den Bos GC. High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats. Am J Physiol Heart Circ Physiol. 1994; 266: H1581–H1587.
Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA, Karp JS, Deutschman CS. Evidence of myocardial hibernation in the septic heart. Crit Care Med. 2005; 33:2752–2756.
Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. A circulating myocardial depressant substance in humans with septic shock: septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest. 1985; 76: 1539–1553.
Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock. 1999; 13: 174–180.
Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989; 321: 280–287.
Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo JE. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest. 1989; 95: 1072–1080.
Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E. Administration of anti-TNF antibody improves left ventricular function in septic shock patients: results of a pilot study. Chest. 1992; 101: 810–815.
Fisher CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E; the Soluble TNF Receptor Sepsis Study Group. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N Engl J Med. 1996; 334: 1697–1702.
Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, Zwingelstein C, Lesslauer W, Leighton A; Ro 45-2081 Study Group. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multicenter trial. JAMA. 1997; 277: 1531–1538.
Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal Nogare A, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light RB, Poole L, Allred R, Constant J, Pennington J, Porter S; NORASEPT II Study Group. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet. 1998; 351: 929–933.
Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol. 1998;30: 215–223.
Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.Ann Surg. 1992; 215: 356–362.
Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105: 575–580.
Liu SF, Newton R, Evans TW, Barnes PJ. Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond). 1996; 90: 301–306.
Fletcher JR, Ramwell PW. Modification, by aspirin and indomethacin, of the haemodynamic and prostaglandin releasing effects of E. coli endotoxin in the dog.Br J Pharmacol. 1977; 61: 175–181.
Bernard GR, Wheeler AP, Russel JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christmann BW, Dupont WD, Higgins SB, Swindell BB; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997; 336: 912–918.
Tunctan B, Altug S, Uludag O, Demirkay B, Abacioglu N. Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. Pharmacol Res. 2003; 48: 37–48.
Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ. Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol.2001; 281: L537–L543.
Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. J Cardiovasc Pharmacol. 1998; 31: S541–S544.
Yang LL, Gros R, Kabir MG, Sadi A, Gotlieb AI, Husain M, Stewart DJ. Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation. 2004; 109: 255–261.
Konrad D, Oldner A, Rossi P, Wanecek M, Rudehill A, Weitzberg E. Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock. Crit Care Med. 2004; 32: 1192–1199.
Schulz R, Rassaf T, Massion PB, Kelm M, Balligand JL. Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis. Pharmacol Ther. 2005; 108: 225–256.
Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Modder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J. 2006; 27: 1699–1705.
Kelm M, Schafer S, Dahmann R, Dolu B, Perings S, Decking UK, Schrader J, Strauer BE. Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation. Cardiovasc Res. 1997; 36: 185–194.
Merx MW, Godecke A, Flogel U, Schrader J. Oxygen supply and nitric oxide scavenging by myoglobin contribute to exercise endurance and cardiac function.FASEB J. 2005; 19: 1015–1017.
Preiser JC, Zhang H, Vray B, Hrabak A, Vincent JL. Time course of inducible nitric oxide synthase activity following endotoxin administration in dogs. Nitric Oxide. 2001; 5: 208–211.
Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, Wildhirt SM, Schulz R. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol. 2002; 283: H1108–H1115.
Hwang TL, Yeh CC. Hemodynamic and hepatic microcirculational changes in endotoxemic rats treated with different NOS inhibitors. Hepatogastroenterology.2003; 50: 188–191.
Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000;87: 241–247.
Connelly L, Madhani M, Hobbs AJ. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived NO in vivo. J Biol Chem. 2005; 280: 10040–10046.
Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Harken AH, Meng X. ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation. Am J Physiol Regul Integr Comp Physiol.2002; 283: R477–R486.
Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Meng X, Harken AH. Vascular cell adhesion molecule-1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.Surgery. 2001; 130: 319–325.
Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004; 32: 1928–1948.
van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996; 97: 713–719.
van der Poll T, Levi M, Dentener M, Jansen PM, Coyle SM, Braxton CC, Buurman WA, Hack CE, ten Cate JW, Lowry SF. Epinephrine exerts anticoagulant effects during human endotoxemia. J Exp Med. 1997; 185: 1143–1148.
Lemaire L, de Kruif M, Giebelen IA, Levi M, van der Poll T, Heesen M. Dobutamine does not influence inflammatory pathways during human endotoxemia.Crit Care Med. 2006; 34: 1365–1371.
Leone M, Boyadjiev I, Boulos E, Antonini F, Visintini P, Albanese J, Martin C. A reappraisal of isoproterenol in goal-directed therapy of septic shock. Shock. 2006;26: 353–357.
Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, Takeda J. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med. 2005; 33: 2294–2301.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344: 699–709.
Tonelli M, Isles C, Craven T, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, West M, Packard C, Curhan GC. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation. 2005; 112: 171–178.
Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report.Circulation. 2005; 112: 357–363.
Zhang L, Zhang ZG, Ding GL, Jiang Q, Liu X, Meng H, Hozeska A, Zhang C, Li L, Morris D, Zhang RL, Lu M, Chopp M. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation. 2005; 112: 3486–3494.
Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology. 1996; 34: 51–61.
Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000; 80: 1095–1100.
Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997; 30: 1212–1217.
Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA Jr, Yasukochi Y, Numano F. HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001; 21:1165–1171.
Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol. 1997; 17: 265–272.
Erkkila L, Jauhiainen M, Laitinen K, Haasio K, Tiirola T, Saikku P, Leinonen M. Effect of simvastatin, an established lipid-lowering drug, on pulmonary Chlamydia pneumoniae infection in mice. Antimicrob Agents Chemother. 2005; 49: 3959–3962.
del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, Alegret M, Pena JM, Rodriguez-Zapata M, Alvarez-Mon M, Martinez A, Manes S. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med. 2004;200: 541–547.
Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004; 110: 880–885.
Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet. 2006; 367:413–418.
Panacek EA, Marshall JC, Alberson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004; 32: 2173–2182.
Zeiher BG, Steingrub J, Laterre PF, Dmitrienko A, Fukiishi Y, Abraham E; EZZI Study Group. LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis.Crit Care Med. 2005; 33: 1741–1748.
Grandel U, Hopf M, Buerke M, Hattar K, Heep M, Fink L, Bohle RM, Morath S, Hartung T, Pullamsetti S, Schermuly RT, Seeger W, Grimminger F, Sibelius U. Mechanisms of cardiac depression caused by lipoteichoic acids from Staphylococcus aureus in isolated rat hearts. Circulation. 2005; 112: 691–698.
Bernstein, HL, Pearlman, JD and A. Lev-Ari Alternative Designs for the Human Artificial Heart: The Patients in Heart Failure – Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community
Pearlman, JD and A. Lev-Ari 7/17/2013 Emerging Clinical Applications for Cardiac CT: Plaque Characterization, SPECT Functionality, Angiogram’s and Non-Invasive FFR
Lev-Ari, A. 7/14/2013 Vascular Surgery: International, Multispecialty Position Statement on Carotid Stenting, 2013 and Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD
Lev-Ari, A. 7/9/2013 Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers
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Lev-Ari, A. 6/3/2013 Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care
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The voice of Series A Content Consultant, Justin D Pearlman, MD, PhD, FACC
The leading cause of death and disability from any cause is cardiovascular disease, principally, heart attacks and strokes. Both the heart and brain typically allow only 10 minutes or so of inadequate blood supply before starting a committed course of permanent tissue injury, progressing in severity as time goes by without successful interruption of the disease process. Thus there is great time urgency to get patients to a definitive treatment that can stop the injury and restore adequate nutrient blood supply. Many patients can benefit from a catheterization to identify blockages and insert a small balloon within the blockage to expand the narrow channel, often followed by placement of a stent (wire cage) to maintain the expanded vessel diameter. Chemicals released over time from drug-eluting stents can prevent tissue in growth that may obstruct stents. These emergeny interventions are not always successful. There may be complications from the attempt to access an entry artery, and the blockages may not be amenable to a balloon. When such limitations are encountered, the next chance to help is surgical, with continued time pressure.
The fastest way to make the transition from a diagnostic catheterization to a timely intervention is a hybrid intervention suite that offers non-invasive imaging, catheterization and surgery all in one location. The following articles present the current state of hybrid “do it all” intervention suites. Additional articles address the risks of bad outcomes from such interventions.
Part One
Hybrid Cath Lab/OR Suite for Hybrid Surgery
In ACC.10 and i2 Summit, 59th Annual Scientific Session, 3/14-3/16, 2010, Alfred A. Bove, M.D., Ph.D., F.A.C.C., ACC President addressed the conference attendees:
Welcome to the all-new Hybrid Cath Lab/OR and 3D CV Theater. Recent developments in cardiac surgery and interventional cardiology have led to the creation of integrated, hybrid cath lab/operating rooms (OR), which provide significant advantages in the diagnosis and treatment of patients requiring cardiac procedures—helping to facilitate a rapid-response approach. These multimodality rooms are designed to support a variety of integrated surgical and endovascular procedures. We are excited to provide you with this opportunity to get a first-hand look—and feel—of the latest technologies. We hope you take the time to explore this interactive, multivendor venue. Learning is at the core of the ACC Annual Scientific Session and we invite you to expand your educational experience in this dynamic learning environment.
In the Hybrid Cath Lab/OR Suite, you’ll discover how integrating cutting edge angiographic and surgical equipment and technologies can facilitate a broad range of procedures within one location. Additionally, you will learn how hybrid suites are providing solutions that enable interventionalists and surgeons to work collaboratively to provide the best treatment options for patients. The adjoining 3D CV Theater features presentations by physicians currently performing intravascular and surgical procedures in hybrid suites. Each live presentation pairs a cardiologist with a surgeon, allowing you to hear perspectives from both sides on a variety of hybrid suite procedures and cases. In addition, the Theater offers video presentations of cases from around the world.
The ACC thanks the supporters of the Hybrid Suite for providing us with the opportunity to share this unique learning destination with you.
are perfect examples of procedures that could, and should, be carried out in a hybrid OR. High-risk patients who require less invasive interventions are the best candidates for treatment in a hybrid suite.
As cardiac surgery becomes less invasive, incisions are becoming smaller and smaller, and even totally endoscopic heart surgery is now possible. Cardiac surgeons have started to perform procedures that include catheter-based skills, such as transapical valve replacement. For these operations, surgeons need more sophisticated imaging techniques, fluoroscopy and contrast injections. The hybrid OR offers all these facilities. Perhaps the most obvious and easiest procedure that can be performed in a hybrid OR is coronary revascularization combining coronary artery bypass grafting with on-table intra-operative completion angiography for quality control. If the surgeon detects a problem during the procedure, he or she can revise the graft immediately and thereby prevent potential perioperative and long-term complications. Currently, cardiologists and cardiovascular surgeons have shown special interest in so-called hybrid coronary interventions, which are combinations of minimally invasive coronary artery bypass grafting and percutaneous coronary interventions. In these procedures, cardiovascular surgeons place a left-internal mammary artery bypass graft to the left-anterior descending artery through small incisions (MIDCAB) or completely endoscopically (TECAB), while any remaining obstructed coronary arteries are treated with stents by an interventional cardiologist. This procedure is an attractive alternative to multivessel open coronary artery bypass grafting. Transcatheter heart-valve replacement and repair are especially suited to a hybrid suite because percutaneoustransfemoral and transapical aortic valve repairs include risks that can only be treated successfully by immediate surgical intervention, such as coronary artery obstruction, aortic dissection and aortic perforations.
In addition, endovascular aortic stent grafting for the repair of abdominal aortic aneurysms is a suitable procedure for a hybrid operating room. Endovascular aneurysm repair has become an established alternative to open repair and is increasingly used for thoracic aorta repair as well. Some
emergency procedures for traumatic lesions of the thoracic aorta and
fulminant pulmonary embolism may also be performed in a hybrid OR. Several
pediatric interventions can be carried out in a hybrid suite as well, such as implantation of closure devices for atrial and ventricular septal defects in small children and
In a recent article we reported on the Change in Requirement for Surgical Support by Cath Labs for performance of Nonemergent PCI without Surgical Backup, that increases the autonomy of Interventional Cardiologists. In the Hybrid OR that change is irrelevant since the presence of a Cardiac Surgeon is a fact of the division of labor between the two types of specialties. Cardiac Surgeons are involved with percutaneous transfemoral and transapical aortic valve repairs and intervention for endoscopic aorta, AAA and Thoracic AA grafting.
Cardiovascular hybrid suite is a state-of-the-art operating room equipped with a fully functional catheterization laboratory, thus allowing surgical procedures and catheter-based interventions to be carried out in the same room. Hybrid suites provide a place where treatments traditionally available only in a cath lab and procedures only available in an operating room can be performed together to provide patients with the best available combination of therapies for cardiovascular disease. These multidisciplinary, integrated cardiovascular procedural suites bring the best of two worlds together by combining all the advantages of a modern cath lab with an up-to-date cardiovascular surgery operating room (OR).
Hybrid suites began to evolve in the mid to late 1990s, when some groups of interventional cardiologists started sharing operating rooms with cardiovascular surgeons. The appeal of the hybrid suite concept has grown as have catheter based devices (stents, coils, balloons and lasers) have been developed that enable interventional cardiologists to advance the invasiveness and effectiveness and applications of percutaneous transcatheter interventions. The interest in these suites has also increased as cardiovascular surgeons have developed a variety of techniques for
Minimally invasive procedures, such as minimally invasive direct coronary artery bypass grafting (MIDCAB) or
With the advent of more tools, interventional cardiologists are becoming more like surgeons, and with less invasive tools, cardiovascular surgeons are becoming more like interventionalists. Rather than separating surgical procedures from interventional procedures performed in traditional operating rooms and cath labs, hybrid suites provide a high-tech environment that allows cardiologists and surgeons to work together to offer patients complex, minimally invasive therapies.
Some experts believe that hybrid suites represent the wave of the future in cardiovascular care and that most heart centers will eventually install hybrid suites to offer patients the latest cardiovascular procedures safely and effectively with minimal surgical trauma. The rooms can be costly to build and equip, but if a medical center is considering building a new operating room or cath lab, setting up a hybrid suite makes sense. Medical centers that have a hybrid suite available can clearly differentiate themselves in a positive way from centers that do not have such capabilities.
The Benefits of a Hybrid Suite for Medical Centers
While building a hybrid suite is more expensive than building a traditional operating room or cath lab, a hybrid suite can potentially be used for all types of cardiovascular procedures, including
traditional cardiac and vascular surgery,
interventional coronary procedures,
endovascular aortic procedures and
electrophysiology procedures.
Hybrid suites reinforce the trend in cardiovascular care toward less invasive, comprehensive hybrid procedures. Once a hybrid suite is in place, the demand for its use will likely grow due to increasing indications and referrals for these innovative treatments, many of which are increasingly covered by third-party payers.
Interventional cath labs usually have excellent imaging capabilities but lack the sterile facilities and staff needed for a formal OR, while operating rooms frequently lack high-level imaging equipment. Some of the essential equipment for a hybrid suite includes:
• A state-of-the-art imaging system capable of performing 3D rotational angiography, CT scanning, and ultrasound is advantageous. Floor-mounted and ceiling-mounted systems are available, but many hospitals use ceiling-mounted systems because access to the patient is slightly easier. Some ceiling-mounted systems provide 3D imaging from the surgeon’s position perpendicular to the patient. However, some hospitals prefer floor-mounted systems because having mechanical parts running above the operative field may cause dust to fall, resulting in infections. An important aspect is that the C-arm can be parked away when it is not used. This especially enhances access of the anesthesia team to the patient.
• An operating table that meets the needs of both surgeons and interventionalists by electronically integrating the table with the imaging system is also essential. These tables should have retractable rails for retractors and other surgical tools. To perform 3D imaging on the operating table, the C-arm of the imaging system should allow fast and precise rotation around the patient.
• A variety of other surgical and interventional systems and equipment may also be needed, including a robotic surgical system, a heart-lung machine, an image integration system, an endoscopic imaging system, a radiology display system, an audiovisual system to move images to different monitors and an anesthesia monitoring system, including transesophageal echocardiography. Some equipment like the integrated OR table and the angiography unit need to be fixed parts of the hybrid OR. Some equipment will be mobile in order to maintain some flexibility in workflow.
Philips is one of the world’s leading technology companies, with a long history of practical innovation and visionary design. In healthcare, we are committed to understanding the human and technological needs of patients and caregivers. We believe this understanding will help us deliver solutions that not only enable more confident diagnoses and more efficient delivery of care, but also improve the overall experience of care. We offer equipment, software and services for imaging, patient monitoring, resuscitation and much more. A Hybrid OR can help make life simpler for the interdisciplinary teams who operate in this environment every day. As a world leader in cardiovascular X-ray, Philips has the experience and expertise to deliver the first class technology you need to perform minimally invasive procedures with speed, accuracy and confidence. A long history of innovation has enabled Philips to develop pioneering imaging solutions that really make a difference.
For example, Philips Allura Xper cardiovascular X-ray systems are designed to deliver enhanced imaging with superb performance for all cardiac projections, and our iE33 ultrasound system with Live 3D TEE and QLAB can assist interventional procedures and provide comprehensive quantitative information to support critical decisions. Our cardiology informatics solutions help you manage patient information throughout the cardiovascular care continuum. Philips solutions allow minimally invasive and catheter-based procedures to take place in the same suite as conventional cardiac surgery.
Phillips EchoNavigator – X-Ray and 3-D Ultrasound is described in:
Intuitive Surgical, Inc. is the global technology leader in robotic-assisted, minimally invasive surgery. The company’s da Vinci® Surgical System offers breakthrough capabilities that enable cardiac surgeons to use a minimally invasive approach and avoid median sternotomy.
Content of FDA Warning Letter, following FDA Inspection on dates 04/01/2013 – 05/30/2013 – it discussed in
MAVIG’s specialty is ceiling/boom suspension systems for lighting (exam, surgical and LED), monitor-suspension systems—single, multibank (one to eight) systems and widescreen, overhead radiation shielding and contrast injector adapters. MAVIG also manufactures radiation protection products such as aprons, gloves, table-attachable lower body shields, adjustable- and fixed-height mobile and modular barriers.
Creating a hybrid lab may be complicated, but having an experienced partner that listens makes all the difference. Toshiba’s unique blend of hybrid experience and industry recognized Infinix™-i imaging systems for the Cath Lab.
Hybrid Cath Lab/OR Suite in Leading Hospitals in the US
The Hybrid Cath Lab/OR Suite at New York Presbyterian Hospital/Columbia University Medical Center, New York, NY is presented in
Speakers at 3D CV Theater, 2010 are working in Hospitals where Hybrid Cath Lab/OR Suite are in operations at the present time. The list include the following Hospitals with a Hybrid Cath Lab/OR Suite:
Vanderbilt Medical Center, Nashville, TN
University of Maryland Heart Center, Baltimore, MD
The Heart Center at Nationwide Children’s Hospital, Columbus, Ohio
The Robotic Surgical Center, East Carolina University Department of Surgery, Greenville, N.C.
University of Washington Medicine Regional Heart Center, Seattle, WA
Brigham and Women’s Hospital, Boston, MA
Saint Joseph’s Hospital and Peachtree Cardiovascular and Thoracic Surgery, Atlanta, GA
Emory University Hospital, Atlanta, GA
Beth Israel Deaconess Medical Center, Boston, MA
Boston Medical Center, Boston, MA
Mayo Graduate School of Medicine, Mayo Clinic, Rochester, MN
Lankenau Hospital, Lancaster, PA
Cardiac Non-Invasive Laboratory at Cedars-Sinai Medical Center, Los Angeles, CA
Robotic Surgery at St. Joseph’s Hospital, Atlanta, GA
Speakers at 3D CV Theater, 2010, included the following Cardiovascular Interventionists leading the adoption process of Hybrid Surgery in Hybrid Cath Lab/OR Suite into care modalities for cardiovascular disease:
Johannes O. Bonatti, M.D., is professor of surgery and director of coronary surgery and advanced coronary interventions at the University of Maryland Heart Center, Baltimore. He received his training in general surgery and cardiac surgery at the department of surgery at Innsbruck Medical University in Austria. Prior to his arrival at the University of Maryland, he worked at this institution as an attending surgeon and associate professor. Dr. Bonatti’s main interest is the development of minimally invasive, totally endoscopic coronary artery bypass grafting (TECAB) procedures using robotic technology.
As one of the international leaders in this field, he performed the largest series of robotic TECAB on the arrested heart, including single-, double- and triple-vessel TECAB. He has published significantly on procedure development and the implementation process of completely endoscopic coronary surgery using the da Vinci robotic system. Together with colleagues from interventional cardiology, Dr. Bonatti is working on integrated concepts for treatment of coronary artery disease. He was the first to perform a simultaneous hybrid coronary intervention using TECAB and placement of a coronary stent. He is organizing international meetings on hybrid interventions in cardiovascular medicine (http://www.icrworkshop.com). He has trained heart surgeons from around the world in the use of the da Vinci robot for heart surgery and he has introduced TECAB procedures in Austria, the Czech Republic, Greece, Turkey, India and Australia.
John G. Byrne, M.D., is the William S. Stoney Professor of Cardiac Surgery at Vanderbilt University School of Medicine and chair of the department of cardiac surgery at Vanderbilt Medical Center, Nashville, TN.
Before moving to Vanderbilt, he was associate chief and residency program director in the division of cardiac surgery at Brigham and Women’s Hospital, and associate professor of surgery at Harvard Medical School, Cambridge, MA. A graduate of the University of California, Davis, he received his medical degree in 1987 from Boston University. His postdoctoral training was completed at the University of Illinois affiliated hospitals and Brigham and Women’s Hospital in Boston.
Dr. Byrne is the author of more than 100 scientific articles on cardiac surgery and related areas. His patient care emphasis is
aortic root surgery,
coronary artery disease and
valve surgery
He is board-certified in general surgery and thoracic surgery.
John P. Cheatham, M.D., is director of cardiac catheterization and interventional therapy and codirector of The Heart Center at Nationwide Children’s Hospital, Columbus, Ohio. He is also the George H. Dunlap Endowed Chair in Interventional Cardiology and professor of pediatrics and internal medicine at The Ohio State University College of Medicine. Dr. Cheatham’s area of expertise is transcatheter intervention and hybrid therapy of newborns, children and adults with complex congenital heart disease. He has pioneered several new techniques and devices in non-surgical intervention and is a leader in developing hybrid therapies. He has been a principal investigator in numerous FDA-sponsored clinical trials evaluating non-surgical closure devices and stent therapy over the past two decades. Additionally, Dr. Cheatham designed the first hybrid cardiac catheterization suites and advanced imaging equipment at Nationwide Children’s Hospital. He serves as a consultant to various medical companies and proctors new transcatheter techniques and devices to other physicians around the world. Dr. Cheatham has implemented a formal physician exchange program with two of the leading medical institutions in China. In cooperation with China Red Cross, he is also the foreign director of the International Training Center for treatment of congenital heart disease in poor children. Dr. Cheatham has written more than 120 manuscripts, 16 book chapters, 300 national and international presentations and is co-editor of the book, Complications in Percutaneous Interventions for Congenital and Structural Heart Disease. After graduating from the University of Oklahoma College of Medicine, he completed his residency at Boston Children’s Hospital, followed by a fellowship in Pediatric Cardiology at Texas Children’s Hospital in Houston.
W. Randolph Chitwood, Jr., M.D., is senior associate vice chancellor for health sciences and chief of cardiovascular services at East Carolina University Department of Surgery, Greenville, N.C. Dr. Chitwood is a leading international pioneer in minimally invasive and robotic heart surgery. The Robotic Surgical Center at East Carolina University has trained more than 350 surgeons. His research activities relate to myocardial preservation, simulation in surgery and endoscopic/robotic cardiac surgery. He was the principal investigator of the FDA robotic mitral valve trials that led to approval for use in the U.S. He is the son and grandson of “southwestern Virginia mountain doctors” who set the guidelines for his professional life. He graduated from Hampden-Sydney College and received his medical degree from the University of Virginia. After medical school, he completed the surgical residency at Duke University Medical Center under David C. Sabiston, M.D., an influential surgical educator of the era. At Duke he spent 10 years training in general and cardiothoracic surgery, as well as basic science research.
After his chief residency at Duke in 1984, he was selected to begin and head the new cardiac surgery program at the East Carolina University School of Medicine. Because of his prolific publication record as a resident and clinical acumen, his initial appointment was as a full professor of surgery. Except for a two-year hiatus as the chief of cardiothoracic surgery at the University of Kentucky, he has spent his entire career at East Carolina University, where he also served as chairman of the department of surgery. In 2003, he was named to be in charge of the development of the East Carolina Heart Institute, which now includes an integrated department of cardiovascular sciences as well as a $200 million heart hospital, outpatient, research and education center.
Larry S. Dean, M.D., is director of the University of Washington Medicine Regional Heart Center and is professor of medicine and of surgery at the University of Washington School of Medicine, Seattle. In addition to general cardiology, he is an expert in cardiac catheterization and interventional cardiology. He also conducts research on stents to keep blocked heart arteries open and on ways to prevent restenosis after stents are inserted. He is currently involved in the evaluation of percutaneous aortic valve replacement. Dr. Dean earned his M.D. from the University of Alabama School of Medicine, Birmingham, and served his internship and residency at the University of Washington. He then returned to the University of Alabama Hospital for fellowships in cardiovascular disease and in angioplasty. After nearly 15 years as a faculty member at the University of Alabama, he returned to the University of Washington to direct the Regional Heart Center. He is a fellow of the American College of Cardiology and is board-certified in internal medicine, cardiovascular disease and interventional cardiology. He is also a fellow of the American Heart Association and president-elect of the Society of Cardiovascular Angiography and Interventions.
Andrew Craig Eisenhauer, M.D., is director of the interventional cardiovascular medicine service at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School. His specialties are
interventional cardiology,
vascular medicine and
congenital and inherited diseases.
He earned his medical degree at New York University School of Medicine and served a residency at Peter Bent Brigham Hospital and a fellowship at Massachusetts General Hospital. He is certified in internal medicine, cardiovascular disease and interventional cardiology. His clinical interests are
endovascular therapy,
complex coronary disease,
peripheral vascular disease,
cerebrovascular disease,
congenital heart disease and structural heart disease
Douglas A. Murphy, M.D., is chief of cardiothoracic surgery at Saint Joseph’s Hospital and a cardiothoracic surgeon at Peachtree Cardiovascular and Thoracic Surgery, Atlanta. His areas of interest are robotically assisted heart surgery with an emphasis on repairing the mitral valve rather than replacing it. A graduate of the University of Pennsylvania Medical School, Philadelphia, he served an internship and residency at Massachusetts General Hospital, Boston, and at Emory University, Atlanta.
Khusrow Niazi, M.D., is an assistant professor at Emory University School of Medicine and director of peripheral and carotid intervention at Emory University Hospital Midtown, Atlanta. He earned his medical degree at King Edward Medical College, Lahore, Pakistan, and served an internship at Kettering Medical Center, Dayton, Ohio, and a fellowship at William Beaumont Hospital, Royal Oak, MI. He has published papers on stenting following rotational atherectomy, small vessel stenting for coronary arteries, imaging of lower extremities and treatment of peripheral arterial disease.
Jeffrey J. Popma, M.D., is director of innovations in interventional cardiology, a senior attending physician at Beth Israel Deaconess Medical Center and an associate professor of medicine at Harvard Medical School in Boston. Dr. Popma received his bachelor’s degree in economics from Stanford University, and his M.D. from Indiana University School of Medicine. He completed his internship, residency, chief residency and fellowship at University of Texas Southwestern Medical Center. He also completed an interventional cardiology fellowship at the University of Michigan. Dr. Popma is the past president of the Society for Cardiac Angiography and Intervention and is the co-chair of the ACC Interventional Council. He sits on the editorial boards of several publications, and reviews for several cardiology periodicals. Dr. Popma has more than 300 published peer-reviewed manuscripts.
Dr. Popma also directs the BIDMC Angiographic Core Laboratory and is principal investigator for more than 65 ongoing multicenter device studies within the research laboratory. Over the past 15 years, these trials have included a broad array of new technology, including bare-metal stents, drug-eluting stents, distal-protection devices, total-occlusion devices and carotid and peripheral revascularization procedures. His primary clinical interest currently is the use of percutaneous aortic valve replacement for patients with high-risk aortic stenosis.
Robert S. Poston, M.D., is chief of cardiac surgery at Boston Medical Center and associate professor of cardiothoracic surgery at Boston University School of Medicine. He has a strong background in minimally invasive cardiac bypass surgery and is a pioneer in using robotics, specifically the da Vinci Surgical System, to treat coronary artery disease. A graduate of the Johns Hopkins School of Medicine, Baltimore, Dr. Poston completed a residency in general surgery at the University of California, San Francisco, and continued his training with a research fellowship in cardiothoracic surgery at Stanford University School of Medicine, Palo Alto, CA, and a cardiothoracic residency at the University of Pittsburgh Medical Center.
Charanjit S. Rihal, M.D., is professor of medicine and director of the cardiac catheterization laboratory at Mayo Graduate School of Medicine, Mayo Clinic, Rochester, MN. A graduate of the University of Winnipeg, Dr. Rihal did his residency and fellowship at the Mayo Graduate School of Medicine and also earned an MBA at the Carlson School of Management, University of Minnesota. His medical interests are interventional cardiology, structural heart disease interventions and the management of quality and costs in healthcare.
Timothy A. Shapiro, M.D., is director of the Interventional Cardiology Fellowship Program and campus chief, interventional cardiology, at Lankenau Hospital, Lancaster, PA. A graduate of Yale University School of Medicine, he served his residency and a fellowship at the Hospital of the University of Pennsylvania.
Robert J. Siegel, M.D., is director of the Cardiac Non-Invasive Laboratory at Cedars-Sinai Medical Center, cardiology director of the Cedars-Sinai Marfan Center, and Rexford S. Kennamer, M.D., chair in cardiac ultrasound at Cedars-Sinai Medical Center, Los Angeles. Dr. Siegel is also professor of medicine in residence at the David Geffen School of Medicine at University of California, Los Angeles. He previously served as senior staff fellow in cardiac pathology at the Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, MD. Internationally recognized as one of the leading experts in the field of cardiovascular ultrasound, Dr. Siegel specializes in cardiovascular ultrasound, including transthoracic, transesophageal and intravascular methodologies. His research interests include
valvular heart disease,
therapeutic applications of ultrasound energy,
transesophageal and intraoperative echocardiography, and the
development and use of hand-held portable echocardiographic systems for clinical innovations.
In addition, he is involved with clinical research studies related to the diagnosis, assessment and management of patients with
Marfan syndrome,
hypertrophic cardiomyopathy and
pericardial and valvular heart disease.
Dr. Siegel is a fellow, and has previously served as the president of the California Chapter of the American College of Cardiology and president of the Los Angeles Society of Echocardiography. He has been active in numerous cardiovascular societies, including the American Heart Association, the American College of Cardiology and the American Society of Echocardiography. Dr. Siegel received his medical degree at Baylor College of Medicine, Houston, where he developed an interest in cardiology. He completed his medical residency at Emory University and at Los Angeles County + USC Medical Center. He completed his cardiology fellowship at Harbor-UCLA Medical Center.
Over the last two years Dr. Siegel has worked extensively with live 3D transesophageal echo in the cardiac intervention center and the operating room. He and his echocardiologist colleagues, doctors Shiota, Biner, Tolstrup and Gurudevan, have worked closely at Cedars-Sinai Medical Center in Los Angeles with the interventional cardiologists, doctors Kar and Makkar, as well as with the cardiac surgeons, doctors Trento and Fontana. They use live 3D TEE extensively for the assessment of structural heart disease. In addition, it is used on a regular basis for the guidance of percutaneous procedures for mitral valve e-clip repair, mitral balloon valvuloplasty, aortic and pulmonic valve replacement, left atrial appendage exclusion by the Watchman device as well as for ASD closure.
Sudhir P. Srivastava, M.D., president of the International College of Robotic Surgery at St. Joseph’s Hospital, Atlanta, is a pioneer in performing beating heart totally endoscopic coronary artery bypass surgeries. Previously, he was assistant professor of surgery and director of robotic and minimally invasive cardiac surgery at the University of Chicago Medical Center. Dr. Srivastava specializes in robotically assisted totally endoscopic coronary artery bypass surgery. He has performed approximately 1,000 robotic cardiothoracic surgical procedures, of which 450 have been single- and multivessel beating heart totally endoscopic coronary bypass (BH TECAB) procedures. He has keen interest in hybrid coronary revascularization in TECAB patients to achieve complete revascularization.
Dr. Srivastava has helped launch robotic revascularization programs throughout the world. He has performed numerous live BH TECAB demonstrations both in the U.S. and abroad, and continues to be a presenter and invited speaker at numerous national and international scientific meetings. He earned his medical degree at the Jawahar Lal Nehru Medical College in Ajmer, India and immigrated to the U.S. in 1972. He completed his cardiothoracic surgery residency at the hospitals associated with the University of British Columbia, Vancouver, Canada.
Francis P. Sutter, D.O., F.A.C.S., is clinical professor of surgery at Thomas Jefferson University-Jefferson Medical College, Philadelphia, and chief of cardiothoracic surgery at Lankenau Hospital, Main Line Health System, Wynnewood, PA. A graduate of Philadelphia College of Osteopathic Medicine, his surgical residency and a cardiothoracic fellowship were completed at Thomas Jefferson University Hospital.
Mark R. Vesely, M.D., is an assistant professor of medicine at the University of Maryland School of Medicine. He completed medical school at the George Washington University and postgraduate training—an internal medicine residency and fellowships in cardiovascular disease and interventional cardiology—at the University of Maryland. He is board-certified in internal medicine, cardiovascular disease, nuclear cardiology and interventional cardiology. Dr. Vesely is the associate program director of the Interventional Cardiology fellowship at University of Maryland. His special interests include the partnered approach (interventional cardiologists and cardiac surgeons) for hybrid coronary revascularization and structural heart disease interventions. Additional research interests include investigation of techniques to minimize acute myocardial infarction injury with ventricular-assist devices and adult stem cell therapies.
David X. M. Zhao, M.D., Ph.D., is an associate professor of medicine and cardiac surgery, Harry and Shelley Page Chair in Interventional Cardiology, director of the Cardiac Catheterization Laboratories and interventional cardiology director of the Interventional Cardiology Fellowship Training Program, Vanderbilt University School of Medicine, Nashville, TN. He earned his medical degree at Shanghai Medical University, Shanghai, P.R. China, and his Ph.D. in immunology at Queensland University, Brisbane, Australia. His postdoctoral training was at Zhongshan Hospital, Shanghai Medical University, Shanghai, P.R. China, The Prince Charles Hospital, Brisbane, Australia, and Brigham and Women’s Hospital, Boston.
Cardiac Surgery @ Cleveland Clinic: Traditional OR & Hybrid Cath Lab/OR Suite
Nation #1 for 19 consecutive years – The Heart Center: Miller Family Heart & Vascular Institute @ Cleveland Clinic
The Sydell and Arnold Miller Family Heart & Vascular Institute is one of the largest, most experienced cardiovascular specialty groups in the world. Our physicians are committed to providing the most advanced diagnostic and treatment options, better outcomes and improved quality of life. U.S.News & World Reporthas ranked Cleveland Clinic as the No.1 heart program in America every year since 1995.
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Comparison of the 10-year and 15-year survivals after CABG demonstrated benefit from a change in graft sources used at the Mayo Clinic and widely adapted by others: vascular grafts from the left internal mammary artery (LIMA) instead of just leg veins, for multiple grafts (up to 3), LIMA-to-LAD plus grafts using LIMA or radial artery vs LIMA/saphenous vein (SV).
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Part Three
Invasive Interventions with Complications
In the following article we covered multiple etiologies for cardiovascular complications related to invasive interventions: cardiovascular and peripheral arterial or peri- and post- cardiac surgery of the open heart type.
Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions
Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
This article covers types of Cardiovascular Complications derived from the following THREE types of assault on the Human body, two related to cardiac invasive interventions, the last due to its systemic nature is taking a fatal Cardiac toll: the Sepsis condition causing cardiac failure.
2. Surgical Complication of Non-cardiac surgery type causing cardiac arrest, i.e, Surgery of Joint Replacement causing sepsis causing death or death caused by complications of surgery i.e., blood loss, viral infection, emboli, thrombus, stroke, or cardiogenic shock not related to Cardiovascular and Cardiac invasive interventions
The e-Reader is advised to consider the following expansion on the subject matter carrying the discussion to additional related clinical issues:
Larry H Bernstein, Advanced Topics in Sepsis and the Cardiovascular System at its End Stage
Bernstein, HL, Pearlman, JD and A. Lev-Ari Alternative Designs for the Human Artificial Heart: The Patients in Heart Failure – Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community
AHA, ACC Change in Requirement for Surgical Support: Class IIb -> Class III, Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, Level of Evidence B).
Larry H Bernstein, MD, FCAP, Author, Curator, Volumes 1,2,3,4,5,6 Co-Editor and Author, Volume Two & Five, Co-Editor and Justin Pearlman, MD, PhD, FACC, Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases
Article ID #68: AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B). Published on 7/17/2013
WordCloud Image Produced by Adam Tubman
Voice of content consultant: Justin Pearlman, MD, PhD, FACC
The American Heart Association (AHA) and the American College of Cardiology (ACC) have convened teams of experts to summarize evidence and opinion regarding a wide range of decisions relevant to cardiovascular disease. The system accounts for some of the short comings of “evidence based medicine” by allowing for expert opinion in areas where evidence is not sufficient. The main argument for evidence-based medicine is the existence of surprises, where a plausible decision does not actually appear to work as desired when it is tested. A major problem with adhesion to evidence based medicine is that it can impede adaptation to individual needs (we are all genetically and socially/environmentally unique) and impede innovation. Large studies carry statistical weight but do not necessary consider all relevant factors. Commonly, the AFFIRM trial is interpreted as support that rate control suffices for most atrial fibrillation (AFIB), but half of those randomized to rhythm control were taken off anticoagulation without teaching patients to check their pulse daily for recurrence of AFIB. Thus the endorsed “evidence” may have more to do with the benefits of anticoagulation for both persisting and recurring AFIB and rhythm control may yet prove better than rate control. However, with wide acceptance of a particular conclusion, randomizing to another treatment may be deemed unethical, or may simply not get a large trial due to lack of economic incentive, leaving only the large trial products as the endorsed options. A medication without patent protection, such as bismuth salts for H Pylori infection, lacks financial backing for large trials.
A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology
Reported by Chris Kaiser, Cardiology Editor, MedPage 7/2013
Action Points
Patients with indications for nonemergency PCI who presented at hospitals without on-site cardiac surgery, were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery or at a hospital with on-site cardiac surgery.
The rates of death, myocardial infarction, repeat revascularization, and stroke did not differ significantly between the groups.
Community hospitals without surgical services can safely perform percutaneous coronary intervention (PCI) in low-risk patients — and not refuse higher-risk patients either, the MASS COMM trial found.
Summary
The co-primary endpoint of major adverse cardiac events (MACE) at 30 days occurred at a rate of 9.5% in the 10 hospitals without surgical backup versus 9.4% in the seven hospitals with onsite surgery (P<0.001 for noninferiority), Alice K. Jacobs, MD, of Boston University School of Medicine, and colleagues found.
The other co-primary endpoint of MACE at 12 months was also significant, occurring in 17.3% of patients in hospitals without backup versus 17.8% in centers with surgical services (P<0.001 for non-inferiority), they reported in the study published online by the New England Journal of Medicine. The findings were also reported at the American College of Cardiology meeting.
Study Characteristics and Results
Primary Endpoints
death
myocardial infarction
repeat revascularization
stroke
no significant differences between the two groups at 30 days and at 12 months.
Rate of stent thrombosis at 30 days
similar in both groups (0.6% versus 0.8%) and at 12 months (1.1% versus 2.1%).
Jacobs and colleagues noted that the 2011 PCI guidelines lacked evidence to fully support nonemergent PCI without surgical backup (class IIb, level of evidence B).
CPORT – E trial
Even though those guidelines came out before the results of the CPORT-E trial were published, CPORT-E trial showed similar non-inferiority at 9 months between centers that perform PCI with or without surgical backup in a cohort of nearly 19,000 non-emergent patients. The CPORT-E results were published in the March 2012 issue of the New England Journal of Medicine, and in May three cardiology organizations published an update to cath lab standards allowing for PCI without surgical.
MASS COMM study
To further the evidence, Jacobs and colleagues in 2006 had designed and carried out the Randomized Trial to Compare Percutaneous Coronary Intervention between Massachusetts Hospitals with Cardiac Surgery On-Site and Community Hospitals without Cardiac Surgery On-Site (MASS COMM) in collaboration with the Massachusetts Department of Public Health who collaborated to obtain “evidence on which to base regulatory policy decisions about performing non-emergent PCI in hospitals without on-site cardiac surgery.”
Hospitals without backup surgery were required to perform at least 300 diagnostic catheterizations per year, and operators were mandated to have performed a minimum of 75 PCI procedures per year.
The researchers randomized 3,691 patients to each arm in a 3:1 ratio (without/with backup). The median follow-up was about 1 year.
The median age of patients was 64, one-third were women, and 92% were white. Both groups had similar median ejection fractions at baseline (55%).
The mean number of vessels treated was 1.17 and most patients (84%) had one vessel treated. The mean number of lesions treated was 1.45 and most patients (67%) had one lesion treated.
The indications for PCI were:
1. ST-segment elevated MI (>72 hours before PCI of infarct-related or non–infarct-related artery — 19% and 17%
2. Unstable angina — 45% and 47%
3. Stable angina — 27% and 28%
4. Silent ischemia — 5% and 6%
5. Other — 2.5% and 2.8%
Regarding secondary endpoints, both groups had similar rates of emergency CABG and urgent or emergent PCI at 30 days. Results at 30 days and 12 months were similar for rates of ischemia-driven target-vessel revascularization and target-lesion revascularization. Other endpoints as well were similar at both time points, including
all-cause death
repeat revascularization
stroke
definite or probable stent thrombosis
major vascular complications
Researchers adjusted for a 1.3 greater chance of MACE occurring at a randomly selected hospital compared with another randomly selected hospital and found
the relative risks at 30 days and 12 months “were consistent with those of the primary results” (RR 1.02 and 0.98, respectively).
However, they cautioned that new sites perhaps should be monitored as they gain experience.
A prespecified angiographic review of 376 patients who were in the PCI-without-backup arm and 87 in the other arm showed no differences in
rates of procedural success,
proportion with complete revascularization, or
the proportion of guideline-indicated appropriate lesions for PCI.
Such results show consistent practice patterns between the groups, they noted.
The study had several limitations including the
loss of data for 13% of patients, the
exclusion of some patients for certain clinical and anatomical features, and
not having the power to detect non-inferiority in the separate components of the primary endpoint, researchers wrote.
A simple calculation of patient variables before PCI may help stem the tide of readmission within the first month. Also this week, two blood pressure drugs that benefit diabetics and imaging cardiac sympathetic innervation.
Pre-PCI Factors Predict Return Trip
A new 30-day readmission risk prediction model for patients undergoing percutaneous coronary intervention (PCI) showed it’s possible to predict risk using only variables known before PCI, according to a study published online in Circulation: Cardiovascular Quality and Outcomes.
After multivariable adjustment, the 10 pre-PCI variables that predicted 30-day readmission were older age (mean age 68 in this study), female sex, insurance type (Medicare, state, or unknown), GFR category (less than 30 and 30-60 mL/min per 1.73m2), current or history of heart failure, chronic lung disease, peripheral vascular disease, cardiogenic shock at presentation, admit source (acute and non-acute care facility or emergency department), and previous coronary artery bypass graft surgery.
Additional significant variables post-discharge that predicted 30-day readmission were beta-blocker prescribed at discharge, post-PCI vascular or bleeding complications, discharge location, African American race, diabetes status and modality of treatment, any drug-eluting stent during the index procedure, and extended length of stay.
Article ID #11: Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”. Published on 1/8/2013
WordCloud Image Produced by Adam Tubman
First segment: Interview with Dr. LCR, Cardiac Surgeon,
Interviews with Scientific Leaders Series
This is the first segment on this subject, in the Interviews with Scientific Leaders Series on our Open Access Online Scientific Journal.
This Segment and the following to be published in this Open Access Online Scientific Journal, are based on an e-mail exchange with a prominent Cardiac Surgeon who worked in the US and in China in Cardiac Surgery Theatres. The identity of the surgeon, I shall conceal. The opening segment provides background, the volume of procedures and the general overview of the medical devices in use.
Following segments will be based on an exchange of Question and Answers (Q&A) which I will be presenting to our Surgeon interviewee and his answers to these specific questions.
I plan to cover the following topics:
Cardiac Repair Procedures
Medical Devices in Use
Technology in Hospitals
Surgeons’ Training and
Cardiac Disease Severity
Background
Dr. LCR, M.D., F.R.C.S.(C), F.A.C.S., Cardiothoracic & Vascular Surgery is the Cardiac Surgeon in this Interview with Scientific Leaders.
Dr. LCR was born in Hong Kong, SAR, China and came to the US in 1972 for higher education and became a US citizen since 1979. He is a US medical school graduate, trained general surgeon (ABS re-certified till 12/2014) and Canadian trained cardiothoracic surgeon (ABTS re-certified till 12/2021). Dr. LCR is also a Fellow of The American College of Surgeons (F.A.C.S.) and an active member of The Society of Thoracic Surgeons (STS) since 1996. He practiced cardiothoracic and vascular surgery in the US between 1992 and 2007 when he accepted the invitation of the Foreign Experts Bureau of the Chinese government to teach/work cardiovascular surgery in China and has just returned to the US two month ago.
During those five and a half years in China, Dr. LCR worked at some of the top and largest cardiovascular programs (West China Hospital of Sichuan University at the city of Chengdu, 1,700 cardiac cases/year.
Dr. LCR worked in Guangdong Provincial Cardiovascular Institute at the city of Guangzhou, the third or fourth largest cardiac program in China, with 3,792 cardiac cases in 2011).
Dr. LCR has also authored or co-authored at least 6 scientific articles when he was in China, all published in the US cardiac journals.
Dr. LCR speaks two Chinese dialects fluently and read and write Chinese at an advanced level.
Below, we present the personal observation and opinions regarding “How the Operating Rooms (OR) are equipped and run in China and the US.”
Dr. LCR was professor of thoracic surgery at West China Hospital of Sichuan University from 06/2007 to 04/2008), the largest hospital in China, with 4,200 beds on one campus (there are three other campuses).
The hospital has 80 some OR’s and the out-patient department saw 2.5 million out-patients the year he was there. The department of Cardiac Surgery performed 1,700 cardiac surgical cases in 2007, with 4 OR’s.
All the major US cardiac surgery vendors were represented, prosthetic heart valves, sutures,etc.. For some “Reason” we only used St. Jude Medical‘s mechanical valves, and we must have put in more than 1,200 to 1,400 valves. They were sold to the Chinese patients the same price as they were sold in the US, about US$ 3,000 each (or 21,00 CNY), about 3.6 million USD of biz for St. Jude, just from a division of the hospital.
The top two heart surgery centers are located in Beijing. Fuwei hospital did 9,700 heart surgery, and the other Aszhen hospital did close to 6,000 in 2011.
The last hospital Dr. LCR worked for as an attending/consultant surgeon until September 2012, The Guangdong Provincial General Hospital (2,400 beds)-The Guangdong Provincial Cardiovascular Institute (480 beds) is probably the third or fourth largest heart surgery center in China, did 3,782 cardiac surgical cases in 2011, most likely exceeded 4,000 in 2012.
If you add the coronary stents put in by the cardiologists in China , the biz for the medical device vendors is immense. For every one coronary bypass we did, the cardiologists must have inserted 20 or more stents. Without a doubt — China is and will be the biggest market for a lot of things, including medical devices, and you are going to the right place. Good luck.
The Next segment will present Dr. LCR’s answers to specific questions I will be e-mailing him of the following topics:
Glucose in the ICU — Evidence, Guidelines, and Outcomes
Brian P. Kavanagh, M.B., F.R.C.P.C.
September 7, 2012 (10.1056/NEJMe1209429)
Just over a decade ago, a single-center Belgian study showed that normalization of blood glucose in critically ill patients lowered hospital mortality by more than 30%.1 Although subsequent studies were unable to reproduce these findings, the appeal of such a straightforward intervention was too great to resist: guidelines from professional organizations2,3 were published, and editorial commentary4 highlighted initiatives by the Institute for Healthcare Improvement, the Joint Commission on Accreditation of Healthcare Organizations, and the Volunteer Hospital Association that incorporated tight glucose control as a standard. Indeed, the prestigious Codman Award of the Joint Commission was presented in 2004 for a program of glycemic control in critical care that “saved” patients’ lives.5 Tight glucose control for critically ill patients was in vogue.
The publication in 2009 of a large international trial (the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation [NICE-SUGAR] study6) followed that of several negative trials. The NICE-SUGAR study, which involved more than 6100 patients, showed that tight glycemic control didn’t decrease mortality — it increased it. Most guidelines were hastily revised. However, in the same year a separate study by Vlasselaers et al.7 in pediatric intensive care unit (ICU) patients, most of whom had undergone cardiac surgery, showed that normalizing glucose decreased mortality from 6% to 3%, keeping open the question — at least in critically ill children.
The study by Agus et al.8 now reported in the Journal provides new key data. A total of 980 children (up to 36 months of age) admitted to an ICU after cardiac surgery were randomly assigned to usual care or tight glucose control. The results are clear — there was no significant difference in the incidence of health care–associated infections (the primary outcome) or in any of the secondary outcomes, including survival. Moreover, the rate of hypoglycemia (blood glucose level <40 mg per deciliter [2.2 mmol per liter]) in the intervention group (3%) was far less than that previously reported (25%).7 These findings contrast sharply with those of Vlasselaers et al.,7 who found that secondary infections, length of stay, and mortality were reduced. Faced with contradictory results from two large clinical trials, how does the clinician know which results are correct?
First, biologic plausibility is important in attributing a survival benefit to a specific intervention. In the first pediatric ICU study, the additional deaths in the control group did not appear to be due to causes related to hyperglycemia,7 a finding that suggests that the benefit was unlikely to be reproducible. The current authors, exclusively studying children after cardiac surgery, recognized that mortality in this population is usually due to prohibitive anatomy or surgical challenge; these are circumstances not amenable to correction by metabolic control.
Second, might differences in the target plasma glucose explain the discrepant findings? Agus et al. aimed for a higher target range of plasma glucose in the intervention group (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) than was targeted in the first pediatric study (infants, 50 to 80 mg per deciliter [2.8 to 4.4 mmol per liter]; children, 70 to 100 mg per deciliter [3.9 to 5.6 mmol per liter]).7 Perhaps the lower glucose target is preferable? The weight of evidence is against this, and if this target were used, the incidence and severity of hypoglycemia would have been greater, as previously reported.7Hypoglycemia is never to a patient’s benefit, and its negative impact on neurocognitive development in children is of particular concern.
It seems that — as in adults — claims for survival benefit in critically ill children are incorrect. Furthermore, there is no reason why the effects of glucose control in children would be opposite to those in adults. In aggregate, the data do not support a basis for embarking on a pediatric megatrial.
Assuming the results of the NICE-SUGAR study6 are generalizable, we must be grateful for the future lives saved by avoiding the practice of normalizing glucose in the ICU. At the same time, we should reflect on why a large study with mortality as an end point was needed in the first place.
Perhaps the most important question from a decade of studying glucose control in the ICU is how influential practice guidelines advocating tight glucose control were developed2,3 yet turned out to be harmful — an issue noted in the lay press.9 Guideline writers, reflecting on the experience, must accept that there are multiple sources of clinical knowledge10 and must pay careful attention to trial characteristics — especially study reproducibility — in order to provide advice that genuinely helps clinicians. Clinicians in turn should use guidelines wisely, recognizing that no single source of knowledge is sufficient to guide clinical decisions.10
Is the door closed on studying glucose homeostasis in the critically ill? No, but it should be closed on the routine normalization of plasma glucose in critically ill adults and children.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
This article was published on September 7, 2012, at NEJM.org.
SOURCE INFORMATION
From the Department of Critical Care Medicine and Anesthesia, Hospital for Sick Children, University of Toronto, Toronto.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367 Full Text | Web of Science | Medline
2
American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control. Diabetes Care 2006;29:1955-1962 CrossRef | Web of Science
3
Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 2004;30:536-555 CrossRef | Web of Science | Medline
4
Angus DC, Abraham E. Intensive insulin therapy in critical illness. Am J Respir Crit Care Med 2005;172:1358-1359 CrossRef | Web of Science | Medline
The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-1297 Full Text | Web of Science
7
Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373:547-556 CrossRef | Web of Science | Medline
8
Agus MSD, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012. DOI: 10.1056/NEJMoa1206044.
Tonelli MR, Curtis JR, Guntupalli KK, et al. An official multi-society statement: the role of clinical research results in the practice of critical care medicine. Am J Respir Crit Care Med2012;185:1117-1124 CrossRef | Web of Science
It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.
What is the main incentive for promoting cancer patients’ management based on smart imaging?
It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.
Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.
Screening for cancer:It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:
In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.
In prostate cancer mortality at 11 years of follow-up [2], the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.
The lobbying campaign (see picture below) that AdmeTech (http://www.admetech.org/) is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.
Treatment: Current state of the art in oncology is characterized by a shift in the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.
Quoting from the National cancer institute (http://www.cancer.gov/) website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.
Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.
To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.
Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011
For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.
Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute (www.camcer.gov) estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from www.usatoday.com : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”
With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.
Coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) is used to reconstitute flow into post-stenotic, chronically underperfused myocardium. This post-stenotic myocardium consists of connective tissue scars, dying cardiomyocytes, and hypo-active or chronically hibernating myocardium with microvascular disturbances due to microthrombi and decreased capillary density. When bulk flow is successfully reconstituted by CABG or PTCA, the gradual recovery of microcirculation is considered as decisive for the recovery of mechanical function of surviving post-stenotic myocardium. Traditionally, neovascularization of disturbed microcirculation was considered to result exclusively from the proliferation, migration, and remodeling of fully differentiated endothelial cells (ECs) derived from pre-existing blood vessels. Recently, however, it was demonstrated that circulating, bone marrow-derived endothelial progenitor cells (EPCs) may home to sites of postnatal neovascularization and differentiate into ECs in situ, which is called “vasculogenesis”. Vascular trauma, as it occurs during surgical procedures, or inflammation leads to a cascade of events that result in the chemoattraction of inflammatory cells or other cell types to the site of injury. These blood-borne cells produce pro-angiogenic factors that, in turn, attract other cell types such as circulating EPCs. Systemic inflammatory responses have been described after cardiac surgery with cardiopulmonary bypass (CPB). Contact of the blood components with the artificial surface of the extracorporeal circuit, ischemia-reperfusion injury, endotoxemia, and operative trauma are possible causes for this phenomenon. Trauma has been considered as the critical stimulus for the mobilization of EPCs and proangiogenic vascular endothelial growth factor (VEGF) during CABG. It has been speculated that this mobilization may contribute to the revascularization of injured tissue, which would be of great clinical relevance for a successful outcome of CABG. Presently, there is a strong trend to perform CABG in patients of advanced age. However, experimental data indicate impaired neoangiogenesis in ischemic tissues and impaired re-endothelialization of vascular lesions as a function of advanced age. The mechanisms for this age-dependent impairment of vascular repair are largely unknown. Therefore, we analyzed the influence of age on CABG-induced mobilization of EPCs and cytochemokines with angiogenesis-modulating potential in a cohort of consecutive patients with stable coronary artery disease (CAD) scheduled for elective CABG. Probably, several types of endothelial precursor or progenitor cells have angiogenic potential after homing into traumatic tissue. Therefore, we used two phenotypic markers (CD34 and AC133 or CD133), which are expressed in all EPC types, but in the case of AC133, not in differentiated ECs. This was done to exclude from our analysis any mature or dying ECs with doubtful angiogenic capacity, potentially released from damaged vessels in old patients. In this analysis, we demonstrate that the preoperative number of circulating EPCs in patients with stable CAD is reduced with increasing age, together with decreased plasma VEGF levels. During CABG, mobilization of circulating EPCs could be detected in all patients, but this mobilization remained on a persistently lower level in the older patient group, suggesting that the responsiveness for mobilization of EPCs is impaired with age. Optimized strategies for ex-vivo expansion of those cells might be especially required in the elderly, if transplantation of these cells into poststenotic tissue will develop as a future co-therapy to existing interventions of revascularization.
This study demonstrated that the basal number of circulating EPCs in patients with stable CAD is decreased with increasing age. Furthermore, plasma VEGF levels are reduced with increasing age. This age-associated decrease could not be explained by higher prevalences of other risk factors, such as male gender, diabetes mellitus, hypertension, or hyperlipoproteinemia at older ages nor by any differences in left ventricular function or New York Heart Association classes. The operative trauma of complex cardiac surgery with CPB induced a mobilization in EPCs/ lymphocytes and EPCs/blood in all patients, but this mobilization remained on a persistently lower level in the older patient group, which could not be explained by any differences in the operative procedure (time on CPB, cross-clamping time, or number of grafts) or in the operation-induced increase in cytochemokines with a reported potency for modulation of angiogenesis (IL-6, IL-8, and IL-10). Similar age-associated losses in the number of circulating endothelial-related progenitor cells in patients undergoing CABG have not been reported so far. In 45 male subjects without a history of cardiovascular disease, the Framingham risk score and impairment of endothelium-mediated, flow-dependent brachial artery dilation were strong predictors of depressed numbers in circulating progenitor cells with colony-forming capacity. In a mixed group of healthy probands and CAD patients, Vasa et al. reported age-associated losses in circulating cells positive for CD34_ and KDR_, which may include progenitor cells and mobilized ECs. In their cohort, smoking was a strong predictor of lowered values in CD34_/KDR_ cells, independent of age. In the patients, self-reported smoking status, which is notoriously unreliable before cardiac surgery, could not be verified by interrogations of spouses or relatives. This may explain why we could not detect an effect of smoking on circulating EPCs. The reasons for the age-associated losses in circulating EPCs remain unknown at present. In this study, there was an age-independent correlation of circulating EPCs with plasma VEGF levels. Circulating or transplanted EPCs contribute to post-ischemic neovascularization in animal experiments and patients, and angiogenic factors like VEGF and PlGF are involved in this neovascularization. In animals, advanced age is associated with attenuated post-ischemic neovascularization and attenuated local induction of VEGF. Similarly, arterial re-endothelialization after vascular trauma is attenuated in old animals in which trauma-induced local VEGF expression is lower and local VEGF supplementation rescues vascular healing. Experimental elevation of plasma VEGF in mice by inoculation with adenoviral vectors induced rapid mobilization of endothelial precursor cells. Therefore, it is tempting to propose that lowered VEGF levels in the elderly patients are the reason for lowered circulating EPCs. However, this causality remains to be proven for basal steady-state levels, and the cause of depressed circulating VEGF levels in elderly patients remains unknown. In experimental studies, hypoxia-inducible factor-1 stabilization by hypoxia, which mediates hypoxic VEGF expression, is attenuated in cells from old animals. This might be relevant for the attenuated and retarded CABG-induced activation of plasma VEGF in older patients. However, this may be less relevant for the age-associated lowering in basal VEGF levels before surgery. Local and systemic inflammation by vascular trauma is considered an important contributor of post-ischemic neovascularization. In the patients, the operative trauma resulted in a substantial mobilization of cytochemokines with angiogenesis-modulating potential, except for IL-18 and PlGF. These observations are in agreement with previous reports. Although none of these activated factors could be directly correlated with the individual increase in EPCs during and after the operation in the patients, it is reasonable to assume that the complex spectrum of inflammatory activation is contributing to the mobilization of surgery-induced EPCs. Similar conclusions have been derived from observations on transient mobilization of KDR_/AC133_ cells in patients after burns or CABG. The kinetics of mobilization in that study differed somewhat from our observations, but the two studies are not directly comparable owing to differences in progenitor cell analysis. It is remarkable that the substantial inflammatory activation during surgery in our study could not abolish age-associated differences in EPC levels. The decline in the fraction of lymphocytes/leukocytes after CPB down to one-quarter that of the baseline value at 12 h after CPB most likely reflects substantial homing of lymphocytes into tissues in response to the systemic inflammatory activation induced by CPB. Homing must also contribute to the decline of circulating EPCs/ blood during this time. Therefore, circulating EPC levels underestimate the amount of EPC mobilization. However, quantification of lymphocyte or EPC homing could not be obtained in our patients. Application of different populations of EPCs or other mononuclear bone marrow cells improves postischemic organ function and microcirculation in animals and patients. However, it is not clear whether the surgery-induced mobilization of EPCs is sufficient for such a contribution. Furthermore, it is unclear whether the EPCs in elderly patients have the same angiogenic potential compared with those of younger patients. The EPCs collected from the circulation can be amplified in vitro. The co-application of amplified EPCs, together with native artery recanalization or bypass grafting, probably will develop as a therapeutic option in the future. The experimental data suggested that such co-therapy is especially desirable in elderly patients. The data suggested that mobilization of such cells for therapeutic application might be more difficult with an increasing age of patients. The inflammatory activation by complex CABG does not offset this age-associated lowering. Therefore, further studies are required for a better understanding of optimized strategies for recruitment, ex-vivo expansion, and retransplantation strategies involving EPCs in aging patients.
Heart attack patients could one day have their heart repaired using their own skin cells. This research focused on the potential use of human pluripotent stem cells such as human embryonic stem cells for the treatment of post-myocardial infarction heart failure and on the utilization of genetically-engineered cell grafts for the treatment of cardiac arrhythmias by modifying the electrophysiological properties. Myocardial cell replacement therapies are hampered by a paucity of sources for human cardiomyocytes and by the expected immune rejection of allogeneic cell grafts. The ability to derive patient-specific human-induced pluripotent stem cells (hiPSCs) may provide a solution to these challenges. That is using a patient’s own cells would avoid the problem of patients’ immune systems rejecting the cells as ‘foreign’. It was aimed to derive hiPSCs from heart failure (HF) patients, to induce their cardiomyocyte differentiation, to characterize the generated hiPSC-derived cardiomyocytes (hiPSC-CMs), and to evaluate their ability to integrate with pre-existing cardiac tissue. Dermal fibroblasts from HF patients were reprogrammed by retroviral delivery of Oct4, Sox2, and Klf4 or by using an excisable polycistronic lentiviral vector. The resulting HF-hiPSCs displayed adequate reprogramming properties and could be induced to differentiate into cardiomyocytes with the same efficiency as control hiPSCs (derived from human foreskin fibroblasts). Gene expression and immunostaining studies confirmed the cardiomyocyte phenotype of the differentiating HF-hiPSC-CMs. Multi-electrode array recordings revealed the development of a functional cardiac syncytium and adequate chronotropic responses to adrenergic and cholinergic stimulation. That is the resulting stem cells were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as those that had been developed from healthy, young volunteers who acted as controls for the study. Next, functional integration and synchronized electrical activities were demonstrated between hiPSC-CMs and neonatal rat cardiomyocytes in co-culture studies. Finally, in vivo transplantation studies in the rat heart revealed the ability of the HF-hiPSC-CMs to engraft, survive, and structurally integrate with host cardiomyocytes. That is it was possible to make the cardiomyocytes develop into heart muscle tissue, which was joined together with existing cardiac tissue and within 48 hours the tissues were beating together. Human-induced pluripotent stem cells thus can be established from patients with advanced heart failure and coaxed to differentiate into cardiomyocytes, which can integrate with host cardiac tissue. This novel source for patient-specific heart cells may bring a unique value to the emerging field of cardiac regenerative medicine. This technology needs to be refined before it can be used for the treatment of patients with heart failure, but these findings are encouraging and take us a step closer to the goal of identifying an effective means of repairing the heart and limiting the consequences of heart failure.
Yankelson, L., Feld, Y., Bressler-Stramer, T., Itzhaki, I., Huber, I., Gepstein, A., Aronson, D., Marom, S., Gepstein, L. 2008. Cell therapy for modification of the myocardial electrophysiological substrate. Circulation 117, 720-731. (http://www.ncbi.nlm.nih.gov/pubmed/18212286)
Huber, I., Itzhaki, I., Caspi, O., Arbel, G., Tzukerman, M., Gepstein, A., Habib, M., Yankelson, L., Kehat, I., Gepstein, L. 2007. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J 21, 2551-2563. (http://www.ncbi.nlm.nih.gov/pubmed/17435178)
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
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