Chao C.-T.,Renal Division |
Wu V.-C.,Renal Division |
Kuo C.-C.,Renal Division |
Lin Y.-H.,Cardiology Division |
And 5 more authors.
Annals of Medicine | Year: 2013
Primary aldosteronism (PA) is the most common secondary form of arterial hypertension, with a particularly high prevalence among patients with resistant hypertension. Aldosterone has been found to be associated with cardiovascular toxicity. Prolonged aldosteronism leads to higher incidence of cardiac events, glomerular hyperfiltration, and potentially bone/metabolic sequels. The wider application of aldosterone/renin ratio as screening test has substantially contributed to increasing diagnosis of PA. Diagnosis of PA consists of two phases: screening and confirmatory testing. Adrenal imaging is often inaccurate for differentiation between an adenoma and hyperplasia, and adrenal venous sampling is essential for selecting the appropriate treatment modality. The etiologies of PA have two main subtypes: unilateral (aldosterone-producing adenoma) and bilateral (micro- or macronodular hyperplasia). Aldosterone-producing adenoma is typically managed with unilateral adrenalectomy, while bilateral adrenal hyperplasia is amenable to pharmacological approaches using mineralocorticoid antagonists. Short-term treatment outcome following surgery is determined by factors such as preoperative blood pressure level and hypertension duration, but evidence regarding long-term treatment outcome is still lacking. However, directed treatments comprising of unilateral adrenalectomy or mineralocorticoid antagonists still potentially reduce the toxicities of aldosterone. Utilizing a physician-centered approach, we intend to provide up-dated information on the etiology, diagnosis, and the management of PA. © 2013 Informa UK, Ltd.
News Article | February 15, 2017
A study from Massachusetts General Hospital (MGH) researchers has found that a pattern of gene variants associated with an "apple-shaped" body type, in which weight is deposited around the abdomen, rather than in the hips and thighs, increases the risk for type 2 diabetes and coronary heart disease, as well as the incidence of several cardiovascular risk factors. The report appears in the February 14 issue of JAMA. "People vary in their distribution of body fat - some put fat in their belly, which we call abdominal adiposity, and some in their hips and thighs," says Sekar Kathiresan, MD, director of the MGH Center for Genomic Medicine, associate professor of Medicine at Harvard Medical School, and senior author of the JAMA report. "Abdominal adiposity has been correlated with cardiometabolic disease, but whether it actually has a role in causing those conditions was unknown. We tested whether genetic predisposition to abdominal adiposity was associated with the risk for type 2 diabetes and coronary heart disease and found that the answer was a firm 'yes'." While several observational studies have reported greater incidence of type 2 diabetes and heart disease among individuals with abdominal adiposity, they could not rule out the possibility that lifestyle factors - such as diet, smoking and a lack of exercise - were the actual causes of increased disease risk. It also could have been possible that individuals in the early stages of heart disease might develop abdominal adiposity because of a limited ability to exercise. The current study was designed to determine whether body type really could increase cardiometabolic risk. To answer that question, the research team applied a genetic approach called mendelian randomization, which measures whether inherited gene variants actually cause outcomes such as the development of a disease. Using data from a previous study that identified 48 gene variants associated with waist-to-hip ratio adjusted for body mass index - an established measure for abdominal adiposity - they developed a genetic risk score. They then applied that score to data from six major genome-wide association studies and to individual data from the U.K. Biobank - a total research group of more than 400,000 individuals - to determine any association between a genetic predisposition to abdominal adiposity and cardiometabolic disease and its risk factors. The results clearly indicated that genetic predisposition to abdominal adiposity is associated with significant increases in the incidence of type 2 diabetes and coronary heart disease, along with increases in blood lipids, blood glucose and systolic blood pressure. No association was found between the genetic risk score and lifestyle factors, and testing confirmed that only the abdominal adiposity effects of the identified gene variants were associated with cardiometabolic risk. "These results illustrate the power of using genetics as a method of determining the effects of a characteristic like abdominal adiposity on cardiometabolic outcomes," says lead author Connor Emdin, DPhil, of the MGH Center for Genomic Medicine and the Cardiology Division. "The lack of association between the body type genetic risk score and confounding factors such as diet and smoking provides strong evidence that abdominal adiposity itself contributes to causing type 2 diabetes and heart disease." Emdin continues, "Not only do these results allow us to use body shape as a marker for increased cardiometabolic risk, they also suggest that developing drugs that modify fat distribution may help prevent these diseases. Future research also could identify individual genes that could be targeted to improve body fat distribution to reduce these risks." Additional co-authors of the JAMA paper are Amit Khera, MD, Pradeep Natarajan, MD, Derek Klarin, MD, and Seyedeh Zekavat, all of the MGH Center for Genomic Medicine; and Allan Hsiao, MPhil, Massachusetts Institute of Technology. Support for the study includes National Institutes of Health grants R01 HL127564, and T32 HL0007734; the Ofer and Shelly Nemirovsky MGH Research Scholar Award; and grants from the Rhodes Trust, and the Donovan Family Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | December 26, 2016
BOSTON - The Affordable Care Act (ACA) instituted financial penalties against hospitals with high rates of readmissions for Medicare patients with certain health conditions. A new analysis led by researchers at Beth Israel Deaconess Medical Center (BIDMC), Harvard T.H. Chan School of Public Health and Massachusetts General Hospital has found that the penalties levied under the law's Hospital Readmissions Reduction Program were associated with reduced readmissions rates and that the poorest performing hospitals achieved the greatest reductions. The research appears online in The Annals of Internal Medicine on December 27, 2016. The Hospital Readmissions Reduction Program was enacted into law in 2010 and implemented in 2012 in response to the high numbers of patients who were readmitted within 30 days of their initial discharge from the hospital after treatment for several common conditions -- including heart failure, pneumonia and acute myocardial infarction (heart attack). While some readmissions may be unavoidable, there was evidence of wide variation in hospitals' readmission rates before the ACA, suggesting that patients admitted to certain hospitals were more likely to experience readmissions compared to other hospitals. "Hospital readmissions represent a significant portion of potentially preventable medical expenditures, and they can take a physical and emotional toll on patients and their families," said co-senior author Robert W. Yeh, MD, MBA, Director of the Smith Center for Outcomes Research in Cardiology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "The Affordable Care Act sought to introduce financial incentives to motivate hospitals, especially the poorest performing ones, to reduce their readmission rates, and only the data could tell us if and how well it worked." "We know that the national hospital readmission rate has been declining since passage of the Affordable Care Act, and our team wanted to assess whether this improvement was driven by the best-performing hospitals alone, or if all groups improved," said first author Jason H. Wasfy, MD, MPhil, who is Director of Quality and Analytics at the Massachusetts General Hospital Heart Center and Instructor in Medicine at Harvard Medical School. The researchers examined Medicare fee-for-service hospitalization data from more than 2,800 hospitals across the country between 2000 and 2013. Based on 30-day readmission rates after initial hospitalization for acute myocardial infarction, congestive heart failure or pneumonia, the researchers categorized hospitals into one of four groups based on the penalties they had incurred under the Hospital Readmissions Reduction Program: highest performance (0% penalty), average performance (greater than 0% but less than 0.5% penalty), low performance (equal to or greater than 0.5% but less than 0.99% penalty), and lowest performance (equal to or greater than 0.99% penalty). "We analyzed data from more than 15 million Medicare discharges," said co-senior author Francesca Dominici, PhD, Professor of Biostatistics and Senior Associate Dean for Research at Harvard T.H. Chan School of Public Health. "We implemented Bayesian hierarchical models to estimate readmission rates for each hospital, accounting for differences in each hospital's patient population. We then used pre-post analysis methods to assess whether there were accelerated reductions in readmission rates within each group after the passage of the reform. It turned out that all groups of hospitals improved to some degree. Notably, we found that it was the hospitals that were the lowest performers before passage of the Affordable Care Act that went on to improve the most after being penalized financially." "For every 10,000 patients discharged per year, the worst performing hospitals - which were penalized the most - avoided 95 readmissions they would have had if they'd continued along their current trajectory before the implementation of the law," added Dominici. "It's a testament to the fact that hospitals do respond to financial penalties, in particular when these penalties are also tied to publicly reported performance goals." "Paying hospitals not just for what they do, but for how well they do - that's still a relatively new way of reimbursing hospitals, and it looks to be effective," Yeh added. This work was funded, in part, by grants from the National Institutes of Health (P01 CA 134294, R01 GM111339, R01 ES024332 and K23 HL 118138-01), as well as support from the Massachusetts General Hospital Cardiology Division's Hassenfeld Scholars Program. Co-authors also include Corwin Matthew Zigler, PhD, Christine Choirat, PhD and Yun Wang, PhD, all of the Department of Biostatistics at the Harvard T.H. Chan School of Public Health. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .
News Article | December 2, 2016
DALLAS - Dec. 1, 2016 -Hospitals in which the administration of epinephrine to patients whose hearts have stopped is delayed beyond five minutes have significantly lower survival rates of those patients, a new study led by a cardiologist at UT Southwestern Medical Center finds. Using data from a large registry, the national team of cardiologists found that nearly 13 percent of patients survived cardiac arrest when epinephrine shots were given within the first five minutes of the heart stopping, compared to about 11 percent when the epinephrine was given after five minutes, independent of all other aspects of care. "That is a 20 percent better survival rate for patients at hospitals where epinephrine is given quickly, which is a big difference," said Dr. Rohan Khera, a Cardiology Division fellow at UT Southwestern and the first author on the study published online in the journal Circulation. Delays in giving the epinephrine shots also had a negative effect on functional recovery, the researchers noted. "These data are important for hospitals and patients. Improving epinephrine administration time, a likely correlate with overall CPR performance, may improve outcomes in cardiac arrest," said Dr. Mark Link, Professor of Internal Medicine at UT Southwestern and a specialist in heart-rhythm disorders, who was not involved in the study. Researchers reviewed more than 100,000 records of patients whose heart stopped while at the hospital, using data from a large national registry run by the American Heart Association. The review involved nearly 550 hospitals across the country. Researchers found considerable variability in how quickly epinephrine, commonly called adrenaline, was administered among the hospitals reviewed. Although individual hospitals were not identified in the study, the data showed that hospitals treating a high volume of cardiac arrest cases tended to administer the adrenaline shots more quickly than those with a lower volume of cases. While TV shows commonly portray doctors dramatically shocking the heart with paddles, this is not the reality for most cardiac arrest patients in hospitals. About 80 percent of in-hospital cardiac arrests are due to causes that cannot be addressed using a defibrillator. These non-shockable heart stoppages are treated with CPR (cardio-pulmonary resuscitation) chest compressions and epinephrine, and these non-shockable cardiac arrests have much lower survival rates. "Treatment options for non-shockable cardiac arrest are so limited that there has been an emphasis on improving current processes," said Dr. Khera. "Administering epinephrine promptly and improving the quality of CPR - these are the easily improved practices, which may be life-saving." Researchers plan to examine processes at hospitals with few delays and compare processes at hospitals with more frequent delays to see if they can identify patterns that could help speed more timely administration of adrenaline shots and whether doing so would improve survival. The multi-center study involved researchers Dr. Saket Girotra of University of Iowa Carver College of Medicine, Dr. Paul Chan of Mid-America Heart Institute and the University of Missouri-Kansas City, and Dr. Michael Donnino of Beth Israel Deaconess Medical Center. Support for the research came from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, and the National Center for Advancing Translational Sciences of the National Institutes of Health. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.
News Article | October 29, 2016
Sonoma Magazine’s Top Doctor survey was submitted to Sonoma County doctors who were then asked which medical specialist they would most often recommend to a loved one, and 327 professionals emerged as top docs in 50 categories of medicine. Among physician peers Dr. Babajanian, Dr. Coleman, Dr. Dunlap and Dr. Korver ranked at the top for cardiology specialists, supporting what the many patients who routinely benefit from the expertise and outstanding cardiovascular services provided by these exemplary physicians already know. The NCMA Cardiovascular Services including Dr. Babajanian, Dr. Coleman, Dr. Dunlap and Dr. Korver is comprised of highly skilled physicians, specialists, nurses and other healthcare professionals dedicated to providing patients’ health care needs. Since 1975, the group has focused on sub-specialization within cardiovascular health to provide services by the most highly trained and experienced physicians and staff. Dr. Masis Babajanian is a fellowship trained cardiologist specializing in Cardiovascular Disease, Internal Medicine, Invasive Cardiology, Nuclear Cardiology and Pacemaker Implants. He received his medical degree from Stanford University School of Medicine and received his fellowship in cardiology from Tulane University School of Medicine, Department of Internal Medicine. Dr. Patrick Coleman is a board certified cardiologist with fellowship training in nuclear and interventional cardiology. He serves as the Medical Director of the Cardiac Catheterization Laboratories for both SRMH and Sutter Santa Rosa, as well as the Director of the Cardiology Section at NCMA. In addition to practicing cardiology at NCMA’s Santa Rosa and Ukiah offices, Dr. Coleman regularly gives lectures to the general public and health providers about maintaining and improving heart health and emergency response. Dr. Thomas Dunlap is a fellowship trained cardiologist specializing in Cardiovascular Disease, Peripheral Vascular, Endovascular Medicine, Interventional Cardiology and Pacemaker Implants. He is the Regional Director of Cardiac and Vascular Services at Santa Rosa Memorial Hospital and Director of the Cardiology Division of NCMA, and Chairman of the Endovascular Committee of Sutter Medical Center of Santa Rosa. He is published in numerous medical journals on cardiovascular health. Dr. Keith Korver is a fellowship trained Cardiothoracic Surgeon from UCSF School of Medicine as well as Pediatric Cardiac Surgery and Cardiac Transplant Surgery. He specializes in general and Cardiothoracic Surgery. NCMA Cardiology is comprised of a team of cardiologists and one cardiothoracic and vascular surgeon —all board-certified in their fields. NCMA’s HeartWorks Cardiac Rehabilitation Center provides each patient with a personal diet and exercise plan supervised by a team of physicians, nurses, and cardiac exercise specialists. In accordance with its practice of providing comprehensive cardiovascular health care, NCMA offers comprehensive care in areas including; NCMA’s services offers cardiac care in three counties, with 11 offices, located in Santa Rosa, Petaluma, Sonoma, Healdsburg, Fort Bragg, Mendocino, Gualala, Ukiah, and Lakeport. To learn more about NCMA Cardiology visit http://www.ncmahealth.com.
Jugdutt B.I.,Cardiology Division |
Jugdutt B.I.,Cardiovascular Research Group |
Jelani A.,Cardiology Division |
Palaniyappan A.,Cardiovascular Research Group |
And 4 more authors.
Circulation | Year: 2010
Background-: Elderly patients with reperfused ST-segment-elevation myocardial infarction are at increased risk for left ventricular remodeling. Extracellular matrix damage has been implicated in early remodeling. We hypothesized that aging results in enhanced early reperfusion injury and left ventricular remodeling after reperfused ST-segment-elevation myocardial infarction and that early therapy initiated at the time of reperfusion with an angiotensin II type 1 receptor blocker such as candesartan attenuates age-related increases in reperfusion injury and remodeling. Methods and results-: We randomized 3 groups of dogs (age, 1 to 2, 2.1 to 5, and 5.1 to 10 years) with reperfused ST-segment-elevation myocardial infarction (90 minutes of ischemia, 2 hours of reperfusion) to therapy with placebo or candesartan (1 mg/kg CV-11974) over 30 minutes from the onset of reperfusion. Reperfusion in placebo groups was associated with aging-related changes in the ischemic zones in markers of damage (increased ischemic injury, infarct size [as percent risk], cardiomyocyte apoptosis, blood flow impairment, no reflow), structural remodeling (increased left ventricular dilation and dysfunction), extracellular matrix remodeling (increased expression of secretory leucocyte protease inhibitor, secreted protein acidic and rich in cysteine, osteopontin, a disintegrin and metalloproteinase-10 and-17, and matrix metalloproteinase-9 and-2), and inflammation (increased inducible nitric oxide synthase, proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and transforming growth factor-β1; decreased antiinflammatory cytokine interleukin-10). Compared with placebo, candesartan attenuated these age-dependent changes. ConclusioN-: Aging results in age-dependent early increases in markers of damage and adverse structural and matrix remodeling after ST-segment-elevation myocardial infarction reperfused after 90 minutes of ischemia, and early therapy initiated at the time of reperfusion with the angiotensin II type 1 receptor blocker candesartan attenuates these changes. This strategy needs clinical confirmation. © 2010 American Heart Association, Inc.
Zareba W.,Cardiology Division |
Zareba W.,Heart Research |
Klein H.,Cardiology Division |
Cygankiewicz I.,Cardiology Division |
And 16 more authors.
Circulation | Year: 2011
Background-This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial. Methods and Results-Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P<0.001) lower in LBBB patients (0.47; P<0.001) than in non-LBBB patients (1.24; P=0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P<0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients. Conclusions-Heart failure patients with New York Heart Association class I or II and ejection fraction ≤30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances). Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. © 2011 American Heart Association. All rights reserved.
Vongpatanasin W.,Hypertension Section |
Wang Z.,Hypertension Section |
Arbique D.,Hypertension Section |
Arbique G.,Radiology |
And 4 more authors.
Journal of Physiology | Year: 2011
In healthy individuals, sympathetic vasoconstriction is markedly blunted in exercising muscles to optimize blood flow to the metabolically active muscle fibres. This protective mechanism, termed functional sympatholysis, is impaired in rat models of angiotensin-dependent hypertension. However, the relevance of these findings to human hypertension is unknown. Therefore, in 13 hypertensive and 17 normotensive subjects we measured muscle oxygenation and forearm blood flow (FBF) responses to reflex increases in sympathetic nerve activity (SNA) evoked by lower body negative pressure (LBNP) at rest and during moderate-intensity rhythmic handgrip exercise. In the normotensives, LBNP caused decreases in oxygenation and FBF (-16 ± 2% and -23 ± 4%, respectively) in resting forearm but not in exercising forearm (-1 ± 2% and -1 ± 3%, respectively; P < 0.05 vs. rest). In the hypertensives, LBNP evoked decreases in oxygenation and FBF that were similar in the resting and exercising forearm (-14 ± 2%vs.-12 ± 2% and -20 ± 3%vs.-13 ± 2%, respectively; P > 0.05), indicating impaired functional sympatholysis. In the hypertensives, SNA was unexpectedly increased by 54 ± 11% during handgrip alone. However, when SNA was experimentally increased during exercise in the normotensives, sympatholysis was unaffected. Treatment for 4 weeks with the angiotensin receptor blocker irbesartan, but not with the thiazide-type diuretic chlorthalidone, restored sympatholysis in the hypertensives. These data provide the first evidence that functional sympatholysis is impaired in hypertensive humans by a mechanism that appears to involve an angiotensin-dependent increase in sympathetic vasoconstriction in the exercising muscles. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.
Price A.,University of Texas Southwestern Medical Center |
Raheja P.,University of Texas Southwestern Medical Center |
Wang Z.,University of Texas Southwestern Medical Center |
Arbique D.,University of Texas Southwestern Medical Center |
And 5 more authors.
Hypertension | Year: 2013
In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors. CLINICAL TRIAL REGISTRATION - : URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787. © 2013 American Heart Association, Inc.
Dai X.,Cardiology Division |
Dai X.,University of North Carolina at Chapel Hill |
Faber J.E.,University of North Carolina at Chapel Hill
Circulation Research | Year: 2010
Rationale: The collateral circulation is tissue-and life-saving in obstructive arterial disease. Disappointing outcomes in clinical trials aimed at augmenting collateral growth highlight the need for greater understanding of collateral biology. Objective: The role of endothelial nitric oxide synthase (eNOS) in forming native (preexisting) collaterals and remodeling in obstructive disease are unknown or controversial issues, respectively. Methods and results: We compared the native collateral circulation in healthy tissue and collateral remodeling after femoral artery ligation (FAL) in wild-type and eNOS-knockout (KO) mice. Perfusion after FAL fell further in adult eNOS-KOs, in association with fewer native collaterals in hindlimb (confirmed in brain). This was not attributable to impaired collateral formation in the embryo-neonate, but rather from collateral loss during growth to adulthood. Compared to wild-type, eNOS-KOs evidenced reduced collateral remodeling, angiogenesis, and flow-mediated dilation of the arterial bed supplying the collaterals, resulting in lower perfusion and greater ischemic injury at all time points over 21 days following FAL. To probe the mechanism for impaired remodeling, we performed genome-wide expression profiling of isolated, remodeling hindlimb collaterals 24 hour after FAL. Upregulation of genes encoding cytokines/chemokines, inflammatory, stress response, and cell cycle proteins was evident in wild-type mice. In contrast, expression was lower in 40 of 44 cell cycle genes in eNOS-KO mice, in association with impaired proliferation of vascular wall cells. Conclusions: Our findings suggest a novel role for eNOS in maintaining native collateral density during natural growth to adulthood and in collateral remodeling in obstructive disease, the latter through regulation of cell proliferation. © 2010 American Heart Association, Inc.