Randall Vagelos, MD

All Publications

• Quantitative Comparison of Microcirculatory Dysfunction in Patients With Stress Cardiomyopathy and ST-Segment Elevation Myocardial Infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kim, H., Tremmel, J. A., Nam, C., Zhou, J., Haddad, F., Vagelos, R. H., Lee, D. P., Yeung, A. C., Fearon, W. F. 2011; 58 (23): 2430-2431

  View details for DOI 10.1016/j.jacc.2011.08.046

  View details for Web of Science ID 000297319700016

  View details for PubMedID 22115653

• Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

  Abstract

  Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

  View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

  View details for Web of Science ID 000297166100008

  View details for PubMedID 21908586

• Measurement Precision in the Optimization of Cardiac Resynchronization Therapy CIRCULATION-HEART FAILURE Turcott, R. G., Witteles, R. M., Wang, P. J., Vagelos, R. H., Fowler, M. B., Ashley, E. A. 2010; 3 (3): 395-404

  Abstract

  Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, the precision of their estimates and the ramifications of an imprecise estimate have not been characterized previously.An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchrony were obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62%-82%). In contrast, impedance cardiography yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values.Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings and a misinterpretation of observed changes over time. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization data in the majority of patients.

  View details for DOI 10.1161/CIRCHEARTFAILURE.109.900076

  View details for Web of Science ID 000277825800009

  View details for PubMedID 20176716

• Dyssynchrony Assessment with Tissue Doppler Imaging and Regional Volumetric Analysis by 3D Echocardiography Do Not Predict Long-Term Response to Cardiac Resynchronization Therapy. Cardiology research and practice Kuppahally, S. S., Fowler, M. B., Vagelos, R., Wang, P., Al-Ahmad, A., Hsia, H., Liang, D. 2010; 2011: 568918-?

  Abstract

  Background. Currently there are no reliable predictors of response to cardiac resynchronization therapy (CRT) before implantation. We compared pre-CRT left ventricular (LV) dyssynchrony by tissue Doppler imaging (TDI) and regional volumetric analysis by 3-dimensional transthoracic echocardiography (3DTTE) in predicting response to CRT. Methods. Thirty-eight patients (79% nonischemic cardiomyopathy) with symptomatic heart failure who underwent CRT were enrolled. Clinical and echocardiographic responses were defined as improvement in one NYHA class and reduction in LV end-systolic volume by ≥15% respectively. Functional status was assessed by Minnesota Living with Heart Failure questionnaire and 6-minute walk distance. Results. In 33 patients, after CRT for 7.86 ± 2.27 months, there were 24 (73%) clinical and 19 (58%) echocardiographic responders. Functional parameters, LV dimensions, volumes and synchrony by TDI and 3DTTE improved significantly in responders. There was no difference in the number of responders and nonresponders when cut-off values for dyssynchrony by different measurements validated in other trials were applied. Area under receiver-operating-characteristic curve ranged from 0.4 to 0.6. Conclusion. CRT improves clinical and echocardiographic parameters in patients with systolic heart failure. The dyssynchrony measurements by TDI and 3DTTE are not comparable and are unable to predict response to CRT.

  View details for DOI 10.4061/2011/568918

  View details for PubMedID 21234100

• Worsening of Left Ventricular End-Systolic Volume and Mitral Regurgitation without Increase in Left Ventricular Dyssynchrony on Acute Interruption of Cardiac Resynchronization Therapy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Kuppahally, S. S., Fowler, M. B., Vagelos, R., Wang, P., Al-Ahmad, A., Paloma, A., Liang, D. 2009; 26 (7): 759-765

  Abstract

  Responders to cardiac resynchronization therapy (CRT) have greater left ventricular (LV) dyssynchrony than nonresponders prior to CRT.We conducted this study to see whether the long term responders have more worsening of LV dyssynchrony and LV function on acute interruption of CRT.We identified 22 responders and 13 nonresponders who received CRT as per standard criteria for 23.73 +/- 7.9 months (median 24.5 months). We assessed the acute change in LV function, mitral regurgitation (MR) and compared LV dyssynchrony in CRT on and off modes.On turning off CRT, there was no significant worsening of LV dyssynchrony in both responders and nonresponders. The dyssynchrony measurements by SPWMD, TDI and 3D echocardiography did not correlate significantly. LVESV increased (p = 0.02) and MR (p = 0.01) worsened in CRT-off mode in responders only without significant change in LVEF or LV dimensions. Discussion andIn long-term responders to CRT, there is alteration in the function of remodeled LV with acute interruption of CRT, without significant worsening of LV dyssynchrony. The role of different echocardiographic parameters in the assessment of LV dyssynchrony remains controversial. Even after long-term CRT reversely remodels the LV, the therapy needs to be continued uninterrupted for sustained benefits.

  View details for DOI 10.1111/j.1540-8175.2008.00887.x

  View details for Web of Science ID 000268457100002

  View details for PubMedID 19558521

• Angina Associated With Left Main Coronary Artery Compression in Pulmonary Hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Perez, V. A., Haddad, F., Vagelos, R. H., Fearon, W., Feinstein, J., Zamanian, R. T. 2009; 28 (5): 527-530

  Abstract

  Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

  View details for DOI 10.1016/j.healun.2008.12.008

  View details for Web of Science ID 000266171400021

  View details for PubMedID 19416787

• Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation AMERICAN HEART JOURNAL Sinha, S. S., Pham, M. X., Vagelos, R. H., Perlroth, M. G., Hunt, S. A., Lee, D. P., Valantine, H. A., Yeung, A. C., Fearon, W. F. 2008; 155 (5)

  Abstract

  Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown.Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18).At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation.Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.

  View details for DOI 10.1016/j.ahj.2008.02.004

  View details for Web of Science ID 000256001500014

  View details for PubMedID 18440337

• Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Fearon, W. F., Shah, M., Ng, M., Brinton, T., Wilson, A., Trernmel, J. A., Schnittger, I., Lee, D. P., Vagelos, R. H., Fitzgerald, P. J., Yock, P. G., Yeung, A. C. 2008; 51 (5): 560-565

  Abstract

  The objective of this study is to evaluate the predictive value of the index of microcirculatory resistance (IMR) in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).Despite adequate epicardial artery reperfusion, a number of patients with STEMI have a poor prognosis because of microvascular damage. Assessing the status of the microvasculature in this setting remains challenging.In 29 patients after primary PCI for STEMI, IMR was measured with a pressure sensor/thermistor-tipped guidewire. The Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade, TIMI frame count, coronary flow reserve, and ST-segment resolution were also recorded.The IMR correlated significantly with the peak creatinine kinase (CK) (R = 0.61, p = 0.0005) while the other measures of microvascular dysfunction did not. In patients with an IMR greater than the median value of 32 U, the peak CK was significantly higher compared with those having values 32 U compared with

  View details for DOI 10.1016/j.jacc.2007.08.062

  View details for Web of Science ID 000252908600007

  View details for PubMedID 18237685

• Cardiogenic Shock. In: D. Daniels, S. Rockson, R. Vagelos (eds.) Concise Cardiology: An Evidence-Based Handbook. Lippincott, Williams and Wilkins. Daniels, D., Brinton, T., Vagelos, R. 2008: 61-68
• Impact of nesiritide on renal function in patients with acute decompensated failure an pre-existing renal dysfunction - A randomized, double-blind, placebo-controlled clinical trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Kao, D., Christopherson, D., Matsuda, K., Vagelos, R. H., Schreiber, D., Fowler, M. B. 2007; 50 (19): 1835-1840

  Abstract

  Our purpose was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure and baseline renal dysfunction.Although nesiritide is approved for the treatment of acute decompensated heart failure, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue.Consecutive patients with acute decompensated heart failure and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive nesiritide (0.01 microg/kg/min with or without a 2-microg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by > or =20% and change in serum creatinine.Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (-0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%).In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with acute decompensated heart failure. (BNP-CARDS trial; http://www.clinicaltrials.gov/ct/show/NCT00186329?order=1; NCT00186329).

  View details for DOI 10.1016/j.jacc.2007.03.071

  View details for Web of Science ID 000250788300003

  View details for PubMedID 17980248

• Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S. S., Valantine, H. A., Weisshaar, D., Parekh, H., Hung, Y. Y., Haddad, F., Fowler, M., Vagelos, R., Perlroth, M. G., Robbins, R. C., Hunt, S. A. 2007; 7 (10): 2388-2395

  Abstract

  The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

  View details for DOI 10.1111/j.1600-6143.2007.01930.x

  View details for Web of Science ID 000249167000022

  View details for PubMedID 17845572

• Changes in coronary anatomy and physiology after heart transplantation AMERICAN JOURNAL OF CARDIOLOGY Hirohata, A., Nakamura, M., Waseda, K., Honda, Y., Lee, D. P., Vagelos, R. H., Hunt, S. A., Valantine, H. A., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Fearon, W. F. 2007; 99 (11): 1603-1607

  Abstract

  Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial and microvascular coronary systems. The timing of the development of abnormalities in these 2 compartments and the correlation between changes in physiology and anatomy are undefined. The invasive evaluation of coronary artery anatomy and physiology with intravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance (IMR) was performed in the left anterior descending coronary artery during 151 angiographic evaluations of asymptomatic heart transplant recipients from 0 to >5 years after heart transplantation (HT). There was no angiographic evidence of significant CAV, but during the first year after HT, fractional flow reserve decreased significantly (0.89 +/- 0.06 vs 0.85 +/- 0.07, p = 0.001), and percentage plaque volume derived by intravascular ultrasound increased significantly (15.6 +/- 7.7% to 22.5 +/- 12.3%, p = 0.0002), resulting in a significant inverse correlation between epicardial physiology and anatomy (r = -0.58, p <0.0001). The IMR was lower in these patients compared with those > or =2 years after HT (24.1 +/- 14.3 vs 29.4 +/- 18.8 units, p = 0.05), suggesting later spread of CAV to the microvasculature. As the IMR increased, fractional flow reserve increased (0.86 +/- 0.06 to 0.90 +/- 0.06, p = 0.0035 comparing recipients with IMRs < or =20 to those with IMRs > or =40), despite no difference in percentage plaque volume (21.0 +/- 11.2% vs 20.5 +/- 10.5%, p = NS). In conclusion, early after HT, anatomic and physiologic evidence of epicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV may be less, because of increased microvascular dysfunction.

  View details for DOI 10.1016/j.amjcard.2007.01.039

  View details for Web of Science ID 000247121700024

  View details for PubMedID 17531589

• Recurrent spontaneous coronary artery dissection with transient left ventricular systolic dysfunction. International journal of cardiology Ardehali, R., Brinton, T. J., Wilson, A. M., Gradman, M., Vagelos, R. H., Lee, D. P. 2007; 116 (2): e48-50

  Abstract

  Spontaneous coronary artery dissection (SCAD) is a potentially life-threatening entity with a variety of clinical presentations. We report a patient who presented with chest pain and angiographic evidence of coronary dissection. Due to the rapid resolution of symptoms and benign-appearing nature of the dissection, no intervention was pursued and the patient was maintained on medical therapy. She represented 2 days later with substernal chest pain, dynamic EKG changes, positive cardiac biomarkers and a transient depression of her left ventricular function.

  View details for PubMedID 16930750

• The effect of gender on mortality or appropriate shock in patients with nonischemic cardiomyopathy who have implantable cardioverter-defibrillators PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Chen, H. A., Hsia, H. H., Vagelos, R., Fowler, M., Wang, P., Al-Ahmad, A. 2007; 30 (3): 390-394

  Abstract

  As heart disease is increasingly recognized in women and as important studies have elucidated the benefit of implantable cardioverter defibrillators (ICDs) in patients with nonischemic cardiomyopathy (NICM), little is known regarding the effect of gender difference on arrhythmic risk in this population. We sought to determine if there are gender differences in arrhythmic risk and potential defibrillator benefit in patients with NICM.The records of 767 consecutive patients who underwent ICD implant at the Stanford Medical Center from 1984 to 2002 were reviewed. Only patients with NICM were considered (n = 201, 26.2%). Of these, 140 patients had clinical follow-up information available. Baseline variables were examined, including age, baseline heart rate, ejection fraction, and medications. We evaluated the time to first shock as well as all-cause mortality in this patient population. Kaplan-Meier survival curves were plotted, a log-rank test was used to evaluate significance, and Cox-proportional hazards test was used for multivariate analysis.There were 88 (62.9%) men and 52 (37.1%) women. Between male and female patients, there were no significant differences in baseline mean age (54.8 +/- 1.9 years vs 53.1 +/- 2.3 years, respectively), ejection fraction (35.2 +/- 2.0% vs 33.3 +/- 2.3%, respectively), and mean left ventricular end-diastolic dimension (6.4 +/- 0.3 cm vs 5.9 +/- 0.2 cm, respectively). Mean follow-up time was 30.8 months. Thirty-two male patients (36.4 +/- 0.05%) received appropriate shocks compared with 20 female patients (38.5 +/- 0.07%). Mean time to the first appropriate shock was 11.9 +/- 3.9 months for male patients and 21.3 +/- 5.8 months for female patients (P = 0.2). Nineteen male patients (21.6 +/- 0.05%) died or received heart transplant during the follow-up period compared with 6 female patients (11.5 +/- 0.04%) (P = 0.11).Male and female patients with NICM who received ICDs had similar rate of appropriate shock and mortality. In this population gender does not appear to be an important risk factor for mortality or arrhythmic events.

  View details for Web of Science ID 000244886500013

  View details for PubMedID 17367359

• Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease JOURNAL OF CLINICAL ONCOLOGY Heidenreich, P. A., Schnittger, I., Strauss, H. W., Vagelos, R. H., Lee, B. K., Mariscal, C. S., Tate, D. J., Horning, S. J., Hoppe, R. T., Hancock, S. L. 2007; 25 (1): 43-49

  Abstract

  Incidental cardiac irradiation during treatment of thoracic neoplasms has increased risks for subsequent acute myocardial infarction or sudden cardiac death. Identifying patients who have a high risk for a coronary event may decrease morbidity and mortality. The objective of this study was to evaluate whether stress imaging can identify severe, unsuspected coronary stenoses in patients who had prior mediastinal irradiation for Hodgkin's disease.We enrolled 294 outpatients observed at a tertiary care cancer treatment center after mediastinal irradiation doses 35 Gy for Hodgkin's disease who had no known ischemic cardiac disease. Patients underwent stress echocardiography and radionuclide perfusion imaging at one stress session. Coronary angiography was performed at the discretion of the physician.Among the 294 participants, 63 (21.4%) had abnormal ventricular images at rest, suggesting prior myocardial injury. During stress testing, 42 patients (14%) developed perfusion defects (n = 26), impaired wall motion (n = 8), or both abnormalities (n = 8). Coronary angiography showed stenosis 50% in 22 patients (55%), less than 50% in nine patients (22.5%), and no stenosis in nine patients (22.5%). Screening led to bypass graft surgery in seven patients. Twenty-three patients developed coronary events during a median of 6.5 years of follow-up, with 10 acute myocardial infarctions (two fatal).Stress-induced signs of ischemia and significant coronary artery disease are highly prevalent after mediastinal irradiation in young patients. Stress testing identifies asymptomatic individuals at high risk for acute myocardial infarction or sudden cardiac death.

  View details for DOI 10.1200/JCO.2006.07.0805

  View details for Web of Science ID 000243725900009

  View details for PubMedID 17194904

• Emerging therapies for the management of decompensated heart failure - From bench to bedside JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY DeGoma, E. M., Vagelos, R. H., Fowler, M. B., Ashley, E. A. 2006; 48 (12): 2397-2409

  Abstract

  While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.

  View details for DOI 10.1016/j.jacc.2006.08.039

  View details for Web of Science ID 000242916100001

  View details for PubMedID 17174176

• Successful removal of a paradoxical coronary embolus using an aspiration catheter NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE Wilson, A. M., Ardehali, R., Brinton, T. J., Yeung, A. C., Vagelos, R. 2006; 3 (11): 633-636

  Abstract

  A 28-year-old man presented at hospital with persistent pain in his chest and left arm, a paced rhythm on electrocardiography and elevated levels of cardiac enzymes. He was known to have patent foramen ovale and a dual-chamber pacemaker, which had been implanted following electrophysiological ablation to treat supraventricular tachycardia 3 years previously. The patient did not have a history of cardiovascular risk factors, recent travel, immobilization or clinical features of infection, and he was not taking any medication.Electrocardiography, cardiac enzyme studies, coronary angiography and transthoracic echocardiography.Acute myocardial infarction, paradoxical coronary embolus and patent foramen ovale.Coronary aspiration embolectomy and systemic anticoagulation.

  View details for DOI 10.1038/ncpcardio0681

  View details for Web of Science ID 000241556000012

  View details for PubMedID 17063168

• Left ventricular dyssynchrony does not deteriorate acutely on cessation of cardiac resynchronization therapy in long term responders 10th Annual Scientific Meeting of the Heart-Failure-Society-of-America Kuppahally, S., Fowler, M., Wang, P., Vagelos, R., Al-Ahmad, A., Paloma, A., Liang, D. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2006: S76–S76

  View details for Web of Science ID 000240205000246

• Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic investigation for transplant arteriopathy II (PITA II) study JOURNAL OF HEART AND LUNG TRANSPLANTATION Fearon, W. F., Hirohata, A., Nakamura, M., Luikart, H., Lee, D. P., Vagelos, R. H., Hunt, S. A., Valantine, H. A., Fitzgerald, P. J., Yock, P. G., Yeung, A. C. 2006; 25 (7): 765-771

  Abstract

  Investigating changes in coronary physiology that occur after cardiac transplantation has been challenging. Simultaneous and independent assessment of the epicardial artery by measuring fractional flow reserve (FFR) and of the microvasculature by calculating the index of microvascular resistance (IMR) with a single coronary pressure wire may be useful.Twenty-five asymptomatic patients with normal coronary angiograms underwent FFR, thermodilution-derived IMR and coronary flow reserve (CFR) and intravascular ultrasound (IVUS) evaluation soon after cardiac transplantation and 1 year later.FFR significantly worsened (0.90 +/- 0.05 at baseline to 0.85 +/- 0.06 at 1 year, p = 0.004). FFR correlated strongly with percent plaque volume as measured by IVUS (r = -0.58, p < 0.0001). IMR improved significantly (29.2 +/- 15.9 at baseline to 19.3 +/- 7.6 units at 1 year, p = 0.007). CFR increased, but not significantly (2.6 +/- 1.4 at baseline to 3.2 +/- 1.2 at 1 year, p = not significant). Diabetes and donor heart ischemic time independently predicted baseline IMR. Treatment with rapamycin independently predicted FFR at 1 year.New coronary physiologic measures, FFR and IMR, show that epicardial artery physiology worsens and correlates with anatomic changes, whereas microvascular physiology improves during the first year after cardiac transplantation. CFR, the traditional method for evaluating coronary circulatory physiology, did not identify these changes.

  View details for DOI 10.1016/j.healun.2006.03.003

  View details for Web of Science ID 000239019700003

  View details for PubMedID 16818118

• Rapamycin therapy improves coronary physiology after cardiac transplantation 55th Annual Scientific Session of the American-College-of-Cardiology Sinha, S. S., Lee, D. P., Pham, M. X., Vagelos, R. H., Hunt, S. A., Valentine, H. A., Yeung, A. C., Fearon, W. F. ELSEVIER SCIENCE INC. 2006: 51A–51A

  View details for Web of Science ID 000235530400222

• Diastolic dysfunction after mediastinal irradiation AMERICAN HEART JOURNAL Heidenreich, P. A., Hancock, S. L., Vagelos, R. H., Lee, B. K., Schnittger, I. 2005; 150 (5): 977-982

  Abstract

  Mediastinal irradiation is known to cause cardiac disease, but its effect on left ventricular diastolic function is unknown. The purpose of this study was to determine the prevalence of diastolic dysfunction and its association with prognosis in asymptomatic patients after mediastinal irradiation.We recruited 294 patients who had received at least 35 Gy to the mediastinum for treatment of Hodgkin disease. Each patient underwent resting echocardiography, stress echocardiography, and nuclear scintigraphy. Survival free from cardiac events was determined during 3.2 years of follow-up.The mean age of the included patients was 42 years, and 49% were male. Adequate measurements of diastolic function were obtained in 282 (97%) patients. Diastolic dysfunction was considered mild in 26 (9%) and moderate in 14 (5%). Exercise-induced ischemia was more common in patients with diastolic dysfunction (23%) than those with normal diastolic function (11%, P = .008). After adjustment for patient demographics, clinical characteristics, and radiation history, patients with diastolic dysfunction had worse event-free survival than patients with normal function (hazard ratio 1.66, 95% CI 1.06-2.4).There is a high prevalence of diastolic dysfunction in asymptomatic patients after mediastinal irradiation, and the presence of diastolic dysfunction is associated with stress-induced ischemia and a worse prognosis. Screening with Doppler echocardiography may be helpful in identifying patients at risk for subsequent cardiac events.

  View details for DOI 10.1016/j.ahj.2004.12.026

  View details for Web of Science ID 000233478800024

  View details for PubMedID 16290974

• Lymphocytic myocarditis after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Weinkauf, J., Walia, R., Berry, G. J., Vagelos, R., Faul, J. L. 2005; 24 (8): 1163-1165

  Abstract

  This study reports the development of lymphocytic myocarditis in a bilateral lung allograft recipient. A 23-year-old woman developed congestive heart failure and severe left ventricular dysfunction 32 months after a bilateral lung allograft for cystic fibrosis. She had taken oral acyclovir for infectious mononucleosis that was diagnosed 11 months previously. Her viral load for Epstein-Barr virus (EBV) increased, and an echocardiogram revealed a left ventricular ejection fraction of 25% and endomyocardial biopsy revealed lymphocytic myocarditis. She received valacyclovir (1 g x 3 times daily) and made a full recovery 6 months later.

  View details for DOI 10.1016/j.healun.2004.07.012

  View details for Web of Science ID 000231300600040

  View details for PubMedID 16102466

• Preoperative cardiac evaluation: mechanisms, assessment, and reduction of risk. Thoracic surgery clinics Ashley, E. A., Vagelos, R. H. 2005; 15 (2): 263-275

  Abstract

  The changing paradigm in cardiovascular disease in which atherosclerotic lesions exist in a spectrum of stable to unstable, the lack of a perfect prediction tool, and the paucity of randomized controlled data on appropriate intervention make protection of cardiac patients undergoing thoracic surgery challenging. Nociception-related sympathetic drive combines with inflammatory stimuli and the cardiodepressant effects of anesthesia to create a window of maximum risk in the early postoperative period (8-24 hours), and although multivariate models have shown that a combination of surgery-specific risk, patient-specific cardiovascular history, and estimated functional capacity best determine the need for further investigation, the optimal choice of investigation is unclear. Exercise or dobutamine stress echocardiography provide the best validated investigations, and in the case of poor images, dobutamine MR imaging is increasingly used. When disease is found, medical and interventional options are available. PCI is often used, but the risk of converting a stable flow-limiting lesion into a less stable non-flow-limiting lesion must be considered, along with a delay for anti-platelet therapy and endothelialization of the stent. Alternatively, medical protection with acute beta-blockade or alpha2-agonists reduces risk (although beta-blockade often is avoided in chronic lung disease, even nonselective agents are safe in patients with non-airways reactive COPD). In addition, it is likely that statin use reduces risk, probably by stabilizing plaques, but patients with cardiac risk are increasingly likely to be taking this medication already. The assessment and management of cardiac risk in the perioperative thoracic surgery patient is challenging. With focused, rational, and individually tailored management; tight monitoring of postoperative pain; and a close working relationship between the surgeon, anesthesiologist, and cardiologist, patient care can be optimized, and risk can be effectively controlled.

  View details for PubMedID 15999524

• Impact of angiotenisin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure AMERICAN HEART JOURNAL Tang, W. H., Vagelos, R. H., Yee, Y. G., Fowler, M. B. 2004; 148 (5): 889-894

  Abstract

  The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear.ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup.At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage.Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

  View details for DOI 10.1016/j.ahj.2004.05.020

  View details for Web of Science ID 000225045100023

  View details for PubMedID 15523323

• "Tako-tsubo-like left ventricular dysfunction": a clinical entity mimicking acute myocardial infarction with a favorable prognosis. American journal of geriatric cardiology Farouque, H. M., Kaltenbach, T., Ako, J., Tremmel, J. A., Fearon, W. F., Yeung, A. C., Vagelos, R. H. 2004; 13 (6): 323-326

  Abstract

  An emotionally-distressed, elderly Caucasian woman presented with chest pain and hypertension. Electrocardiogram showed inferior ST-segment elevation, and an urgent cardiac catheterization was performed. Coronary angiography revealed normal appearing coronary arteries; however, left ventriculography showed extensive left ventricular apical akinesis. The patient had a mild rise in cardiac enzyme levels indicative of myocardial injury. She was discharged after an uncomplicated in-hospital course. One month later, the left ventricular wall motion abnormality had improved. In this report, the authors discuss this compilation of findings known as tako-tsubo-like left ventricular dysfunction.

  View details for PubMedID 15538070

• Simultaneous assessment of fractional and coronary flow reserves in cardiac transplant recipients - Physiologic investigation for transplant arteriopathy (PITA study) CIRCULATION Fearon, W. F., Nakamura, M., Lee, D. P., Rezaee, M., Vagelos, R. H., Hunt, S. A., Fitzgerald, P. J., Yock, P. G., Yeung, A. C. 2003; 108 (13): 1605-1610

  Abstract

  The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy.In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFRthermo) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88+/-0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was < or =0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (r=0.55, P<0.0001). The average CFRthermo was 2.5+/-1.2; in 47% of cases, CFRthermo was < or =2.0. In 14%, the FFR was normal (> or =0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction.FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.

  View details for DOI 10.1161/01.CIR.0000091116.84926.6F

  View details for Web of Science ID 000185624500027

  View details for PubMedID 12963639

• Physiologic interrogation of transplant arterioparthy: Final results 52nd Annual Scientific Session of the American-College-of-Cardiology Fearon, W. F., Nakamura, M., Lee, D. P., Rezaee, M., Vagelos, R. H., Hunt, S. A., Fitzgerald, P. J., Yock, P. G., Yeung, A. C. ELSEVIER SCIENCE INC. 2003: 29A–29A

  View details for Web of Science ID 000181669500129

• Physical activity patterns and exercise performance in cardiac transplant recipients. Journal of cardiopulmonary rehabilitation Myers, J., Gullestad, L., Bellin, D., Ross, H., Vagelos, R., Fowler, M. 2003; 23 (2): 100-106

  Abstract

  Cardiac transplantation (CTX) improves exercise tolerance, but CTX recipients still achieve only 50% to 70% of normal values for exercise capacity. Among the factors suggested to explain the reduced exercise tolerance in CTX recipients is deconditioning. Little is known about the relation between physical activity patterns and exercise test responses in CTX patients.Forty-seven CTX patients (mean age 47 +/- 12 years; mean 4.8 +/- 3.0 years after CTX) underwent maximal exercise testing and assessment of current and past physical activity patterns using a questionnaire. Energy expenditure from recreational and occupational activities over the last year and for adulthood were expressed in kcal/week and correlated with peak oxygen consumption (VO(2)), VO(2) at the ventilatory threshold, and the percentage of age-predicted peak VO(2) achieved.The patients reported expending a mean of approximately 1100 kcal/week in recreational activity, suggesting a moderate level of physical activity is maintained after CTX. The mean peak VO(2) achieved for the group was 17.2 +/- 5.2 mL/kg/min, corresponding to 59% +/- 14% of age-predicted exercise capacity. Significant but modest associations were observed between recreational energy expenditure during the last year and percentage of age-predicted peak VO(2) achieved (r = 0.34, P <.01), and VO(2) at the ventilatory threshold (r = 0.45, P <.01). Energy expenditure from blocks walked and stairs climbed per week was modestly associated with peak VO(2) (r = 0.36, P <.05), percentage of predicted peak VO(2) achieved (r = 0.39, P <.01), and VO(2) at the ventilatory threshold (r = 0.42, P <.01). Exercise capacity was poorly related to occupational and recreational activities when expressed as average weekly energy expended throughout adulthood.Post-CTX patients maintain a moderately active lifestyle. Measures of exercise tolerance generally are related to recent daily recreational activities in CTX patients, but these associations are modest. The many physiologic factors unique to CTX recipients likely play a more important role than deconditioning in determining exercise tolerance in these patients.

  View details for PubMedID 12668931

• Physiologic interrogation of transplant arteriopathy American-Heart-Association Abstracts From Scientific Sessions Fearon, W. F., Nakamura, M., Lee, D. P., Rezaee, M., Vagelos, R. H., Hunt, S. A., Yock, P. G., Yeung, A. C. LIPPINCOTT WILLIAMS & WILKINS. 2002: 591–91

  View details for Web of Science ID 000179142702958

• Acute aortic syndrome: a case presentation and review of the literature VASCULAR MEDICINE Lissin, L. W., Vagelos, R. 2002; 7 (4): 281-287

  Abstract

  Aortic disease can present as an acute chest pain syndrome. Although aortic dissection is the most common etiology, other processes such as intramural hematoma (IMH) and penetrating atherosclerotic ulcers are being increasingly recognized. They can all be accurately identified by computed tomography (CT) imaging or transesophageal echocardiography. The overlap between these processes regarding definition and mechanism is controversial. Treatment for all three conditions has thus far been dictated by location, wherein ascending or arch involvement (Stanford type A) necessitates surgery and descending disease (type B) is treated medically. Small studies suggest that subgroups of type A IMH may be treated medically with good outcomes.

  View details for DOI 10.1191/1358863x02vm450cr

  View details for Web of Science ID 000182268300007

  View details for PubMedID 12710844

• Early use of statins in acute coronary syndromes. Current cardiology reports Spin, J. M., Vagelos, R. H. 2002; 4 (4): 289-297

  Abstract

  This review examines the use of HMG-CoA reductase inhibitor (statin) medications early in the clinical course of acute coronary syndrome. Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for acute coronary syndrome (ACS), patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.

  View details for PubMedID 12052268

• Reversal of phen-fen associated valvular regurgitation documented by serial echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Vagelos, R., Jacobs, M., Popp, R. L., Liang, D. 2002; 15 (6): 653-657

  Abstract

  We report a case of anorexigen-associated moderate to severe aortic and mitral regurgitation in which the regression of lesions was marked and well documented over more than 2 years. The stability of our patient, as well as the degree of regression of regurgitation documented in our patient, and others, suggests it is prudent both to observe such patients and to avoid operation until such observation has been carried out.

  View details for DOI 10.1067/mje.2002.117864

  View details for Web of Science ID 000176263900010

  View details for PubMedID 12050608

• Clinical assessment in ischaemic cardiomyopathy NUCLEAR MEDICINE COMMUNICATIONS Putz, E., Vagelos, R. 2002; 23 (4): 341-345

  Abstract

  Despite the trend of decreasing death rates attributable to ischaemic heart disease and stroke, the prevalence of heart failure and the resultant death rates in the United States have almost tripled between 1974 and 1994 [1]. Coronary artery disease is the commonest cause of heart failure in developed countries, accounting for up to 60% of cases. Advances in medical therapy, particularly the use of angiotensin-converting enzyme inhibitors and beta-blockers, have served to reduce morbidity and mortality in patients with left ventricular (LV) dysfunction due to coronary artery disease [2-5]. However, these improvements have been modest, and despite these therapies, patients with severe ischaemic cardiomyopathy continue to have a high mortality when treated medically. It is increasingly clear that the impaired LV function in these patients is not always an irreversible process. Traditionally, these observations have been made following demonstrable improvements in systolic function after coronary revascularization procedures. Diagnostic testing to evaluate the presence and extent of viable myocardium has therefore become an important component of the clinical assessment of patients with chronic coronary artery disease and LV dysfunction.

  View details for Web of Science ID 000175245600007

  View details for PubMedID 11930187

• Reverse remodeling following long-term carvedilol therapy is associated with improvement in survival: The Stanford Carvedilol Echocardiographic Registry Tang, W. H., Larson, M. S., Vagelos, R. H., Prikazsky, L., Hu, B. S., Fowler, M. B. ELSEVIER SCIENCE INC. 2002: 141A–141A

  View details for Web of Science ID 000174106700623

• Alternative approach for use of a left ventricular assist device with a thrombosed prosthetic valve JOURNAL OF HEART AND LUNG TRANSPLANTATION Pelletier, M. P., CHANG, C. P., Vagelos, R., Robbins, R. C. 2002; 21 (3): 402-404

  Abstract

  Implantation of a left ventricular assist device is problematic in patients with prosthetic heart valves, due to an increased risk of thrombosis with embolization. This report describes the use of a bovine pericardial patch to close the aortic outflow tract in a patient with a mechanical aortic valve and end-stage cardiomyopathy who required urgent left ventricular assist support. A successful outcome suggests that this technique may be of value in treating similar patients.

  View details for Web of Science ID 000174396600015

  View details for PubMedID 11897531

• Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tang, W. H., Vagelos, R. H., Yee, Y. G., Benedict, C. R., Willson, K., Liss, C. L., Labelle, P., Fowler, M. B. 2002; 39 (1): 70-78

  Abstract

  We sought to compare the neurohormonal responses and clinical effects of long-term, high-dose versus low-dose enalapril in patients with chronic heart failure (CHF).Examination of neurohormonal and clinical responses in patients receiving different doses of angiotensin-converting enzyme (ACE) inhibitors may provide insight into the potential for additional suppression with angiotensin II (AT-II) or aldosterone antagonists.Seventy-five patients with CHF were randomized to receive either high-dose (40 mg/day, n = 37) or low-dose (5 mg/day, n = 38) enalapril over six months. The results from exercise testing, echocardiography, tissue-specific ACE activity and monthly pre- and post-enalapril neurohormonal levels were compared.Despite greater intra-group improvements in plasma renin activity and serum aldosterone levels in the high-dose group, no statistically significant differences were observed between the two groups in all variables, except for serum ACE activity at the end of study. Elevated serum aldosterone and plasma AT-II levels were observed in 35% and 85% of patients, respectively, at 34 weeks, an inter-group difference that was not statistically significant. A trend toward higher levels of tissue-specific ACE activity in the high-dose group compared with the low-dose group at the end of study was observed (p = 0.054). A predefined composite end point of clinical events had a trend toward better improvement in the high-dose group.This study could not demonstrate a difference between high- and low-dose enalapril in terms of serum aldosterone and plasma AT-II suppression, despite a dose-dependent reduction in serum ACE activity. Even at maximal doses of enalapril, elevated serum aldosterone and plasma AT-II levels were frequently observed.

  View details for Web of Science ID 000173007500011

  View details for PubMedID 11755289

• Limited sensitivity of troponin I for detecting acute myocardial infarction six hours after chest pain onset: The CAMMI Study Lee, B. K., Heidenreich, P. A., Chun, S. H., Vagelos, R. H., Green, M., Sussman, H., Schreiber, D. H. LIPPINCOTT WILLIAMS & WILKINS. 2000: 497–97

  View details for Web of Science ID 000090072302412

• Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 mL/kg/min revisited AMERICAN HEART JOURNAL Myers, J., Gullestad, L., Vagelos, R., Do, D., Bellin, D., Ross, H., Fowler, M. B. 2000; 139 (1): 78-84

  Abstract

  Accurately establishing prognosis in severe heart failure has become increasingly important in assessing the efficacy of treatment modalities and in appropriately allocating scarce resources for transplantation. Peak exercise oxygen uptake appears to have an important role in risk stratification of patients with heart failure, but the optimal cutpoint value to separate survivors from nonsurvivors is not clear.Six hundred forty-four patients referred for heart failure evaluation over a 10-year period participated in the study. After pharmacologic stabilization at entrance into the study, all participants underwent cardiopulmonary exercise testing. Survival analysis was performed with death as the end point. Transplantation was considered a censored event. Four-year survival was determined for patients who achieved peak oxygen uptake values greater than and less than 10, 11, 12, 13, 14, 15, 16, and 17 mL/kg/min.Follow-up information was complete for 98.3% of the cohort. During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1- and 5-year survival rates were 90.5% and 73.4%, respectively. Peak ventilatory oxygen uptake (VO(2)) was an independent predictor of survival and was a stronger predictor than work rate achieved and other exercise and clinical variables. A difference in survival of approximately 20% was achieved by dichotomizing patients above versus below each peak VO(2) value ranging between 10 and 17 mL/kg/min. Survival rate was significantly higher among patients achieving a peak VO (2) above than among those achieving a peak VO (2) below each of these values (P <.01), but each cutpoint was similar in its ability to separate survivors from nonsurvivors.Peak VO (2) is an important measurement in predicting survival from heart failure, but whether an optimal cutpoint exists is not clear. Peak VO(2) may be more appropriately used as a continuous variable in multivariate models to predict prognosis in severe chronic heart failure.

  View details for Web of Science ID 000084631300012

  View details for PubMedID 10618566

• Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gullestad, L., Aukrust, P., Ueland, T., Espevik, T., Yee, G., Vagelos, R., Froland, S. S., Fowler, M. 1999; 34 (7): 2061-2067

  Abstract

  We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF).Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated.Seventy-five patients (mean age 52 +/- 11 years) with CHF were randomized between low-(5 m g daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks).All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment.In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.

  View details for Web of Science ID 000083956400034

  View details for PubMedID 10588224

• A genetic locus for ventricular arrhythmia and dilated cardiomyopathy on chromosome 2 Dreher, D., Zhu, X. L., Hoang, K. L., Tan, J. L., Vagelos, R. H., Hunt, S. A., Fowler, M. B., McNally, E. M. LIPPINCOTT WILLIAMS & WILKINS. 1999: 217–17

  View details for Web of Science ID 000083417101120

• Ventricular arrhythmia and dilated cardiomyopathy is linked to chromosome 2. Zhu, X., Dreher, D., Hoang, K., Tan, J., Hunt, S., Vagelos, R. H., Fowler, M., McNally, E. M. CELL PRESS. 1999: A455–A455

  View details for Web of Science ID 000082879802586

• Constrictive pericarditis due to coccidiomycosis ANNALS OF THORACIC SURGERY Faul, J. L., Hoang, K., Schmoker, J., Vagelos, R. H., Berry, G. J. 1999; 68 (4): 1407-1409

  Abstract

  Coccidiomycosis is a fungal infection that rarely causes cardiac disease. Constrictive pericarditis in the setting of disseminated coccidiomycosis can be fatal, despite antifungal therapy and pericardiectomy. We report on a patient with constrictive pericarditis due to localized infection by Coccidioides immitis. The patient underwent successful surgical pericardiectomy and antifungal chemotherapy, and remains well 1 year later.

  View details for Web of Science ID 000083265800076

  View details for PubMedID 10543521

• Relationship between tissue and circulating levels of angiotensin converting enzyme with high and low dose enalapril therapy in heart failure Fowler, M. B., Yee, Y. G., Vagelos, R. H., Willson, K., Prikazsky, L., Mullin, A., Waldman-Boucher, M. LIPPINCOTT WILLIAMS & WILKINS. 1998: 854–54

  View details for Web of Science ID 000076594404486

• Case presentation and review: Constrictive pericarditis WESTERN JOURNAL OF MEDICINE Osterberg, L., Vagelos, R., Atwood, J. E. 1998; 169 (4): 232-239

  View details for Web of Science ID 000076401200015

  View details for PubMedID 9795593

• Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure ANNALS OF INTERNAL MEDICINE Myers, J., Gullestad, L., Vagelos, R., Do, D., Bellin, D., Ross, H., Fowler, M. B. 1998; 129 (4): 286-?

  Abstract

  Accurate prognosis in chronic heart failure has become increasingly important in assessing the efficacy of treatment and in appropriately allocating scarce resources for transplantation. Previous studies of severe heart failure have been limited by short follow-up periods and few deaths.To establish clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients with heart failure.Retrospective study.Hospital-based outpatient heart failure clinic.644 patients referred for evaluation of heart failure over 10 years.Age, cause of heart failure, body surface area, cardiac index, ejection fraction, pulmonary capillary wedge pressure, left ventricular dimensions, watts achieved during exercise, heart rate, maximum systolic blood pressure, and oxygen uptake (VO2) at the ventilatory threshold and at peak exercise were measured at baseline. Univariate and multivariate analyses were done for clinical, hemodynamic, and exercise test predictors of death. A Cox hazards model was developed for time of death.During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1-year and 5-year survival rates were 90.5% and 73.4%, respectively. Resting systolic blood pressure, watts achieved, peak VO2, VO2 at the ventilatory threshold, and peak heart rate were greater among survivors than among nonsurvivors. Cause of heart failure (coronary artery disease or cardiomyopathy) was a strong determinant of death (relative risk for coronary artery disease, 1.73; P< 0.01). By multivariate analysis, only peak VO2 was a significant predictor of death. Stratification of peak VO2 above and below 12, 14, and 16 mL/kg per minute demonstrated significant differences in risk for death, but each cut-point predicted risk to a similar degree.Peak VO2 outperforms clinical variables, right-heart catheterization data, exercise time, and other exercise test variables in predicting outcome in severe chronic heart failure. Direct measurement of VO2 should be included when clinical or surgical decisions are being made in patients referred for evaluation of heart failure or those considered for transplantation.

  View details for Web of Science ID 000075329100004

  View details for PubMedID 9729181

• Serial exercise testing and prognosis in selected patients considered for cardiac transplantation AMERICAN HEART JOURNAL Gullestad, L., Myers, J., Ross, H., Rickenbacher, P., Slauson, S., Bellin, D., Vagelos, R., Fowler, M. 1998; 135 (2): 221-229

  Abstract

  This study sought to examine the predictive value of variables obtained from serial maximal exercise testing, echocardiography, and ejection fraction in patients referred as potential heart transplant candidates.Variables such as peak VO2, left ventricular dimensions, ejection fraction, and hemodynamic measurements are known to predict prognosis in heart failure, but there are few data on the impact of serial measurements of these variables on subsequent mortality.Two hundred sixty-three ambulatory patients with severe heart failure referred as potential candidates for heart transplantation who underwent two exercise tests (mean 7.8 months apart) after optimal medical treatment were identified. At the same two time points, echocardiography was performed in 106 (37%) and ejection fraction was measured in 84 (30%). During a mean follow-up period of 3.9+/-0.1 years, 70 (25%) died and 45 (19%) underwent heart transplantation. Exercise capacity, peak exercise heart rate, and peak exercise systolic blood pressure achieved were all significantly higher among survivors compared with nonsurvivors. Among the survivors a slight increase in peak VO2 and ejection fraction were observed, but there were no significant differences in the changes of any of the measured variables between survivors and nonsurvivors. There were no significant differences in survival between patients with increased versus those with decreased peak VO2, left ventricular dimensions, or ejection fraction.Although peak VO2, left ventricular dimensions, and ejection fraction predict survival, changes in these parameters do not add any prognostic information in patients with severe heart failure who have been stabilized with optimal medical treatment. Routine use of these procedures therefore does not seem to be warranted and should be performed only in the context of a specific clinical situation. Serial measurements of these parameters do not appear to be useful in the risk stratification of patients referred for heart transplantation.

  View details for Web of Science ID 000072129400006

  View details for PubMedID 9489968

• Comparison of high versus low dose enalapril therapy on clinical outcomes and neuroendocrine activation in advanced heart failure Fowler, M. B., Vagelos, R. H., Schroeder, J. S., Benedict, C. R., Willson, K., Boucher, M., Mullin, A., Prikazsky, L. M., Liss, C. L., Labelle, P. LIPPINCOTT WILLIAMS & WILKINS. 1997: 105–

  View details for Web of Science ID A1997YC88000105

• Assessment of left ventricular wall motion abnormalities with the use of color kinesis: A valuable visual and training aid JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Lau, Y. S., Puryear, J. V., Gan, S. C., Fowler, M. B., Vagelos, R. H., Popp, R. L., Schnittger, I. 1997; 10 (6): 665-672

  Abstract

  Accurate interpretation of left ventricular segmental wall motion by echocardiography is an important yet difficult skill to learn. Color-coded left ventricular wall motion (color kinesis) is a tool that potentially could aid in the interpretation and provide semiquantification. We studied the usefulness of color kinesis in 42 patients with a history of congestive cardiomyopathy who underwent two-dimensional echocardiograms and a color kinesis study. The expert's reading of the two-dimensional wall motion served as a reference for comparison of color kinesis studies interpreted by the expert and a cardiovascular trainee. Correlation between two-dimensional echocardiography and the expert's and trainee's color coded wall motion scores were r = 0.83 and r = 0.67, respectively. Reproducibility between reviewers and between operators was also assessed. Interobserver variability for color-coded wall motion showed a correlation of r = 0.78. Correlation between operators was also good; r = 0.84. Color kinesis is reliable and appears promising as an adjunct in the assessment of wall motion abnormalities by echocardiography. It is both a valuable visual aid, as well as a training aid for the cardiovascular trainee.

  View details for Web of Science ID A1997XR35200011

  View details for PubMedID 9282356

• Volume-mediated pulmonary responses in liver transplant candidates CLINICAL TRANSPLANTATION Kuo, P. C., Schroeder, R. A., Vagelos, R. H., Valantine, H., Garcia, G., Alfrey, E. J., Haddow, G., Dafoe, D. C. 1996; 10 (6): 521-527

  Abstract

  Pulmonary hypertension, defined as mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg, is a recognized complication of hepatic dysfunction with portal hypertension and is considered a relative contraindication to liver transplantation. To characterize pulmonary hemodynamic responses in OLT candidates without pre-existing primary pulmonary hypertension, 22 consecutive patients referred for OLT at the Stanford University Hospital underwent prospective right heart catheterization with pressure determinations at baseline and following infusion of 11 crystalloid over 10 min. In addition, EKG, chest X-ray and transthoracic echocardiograms were performed as a part of the routine evaluation. Eleven non-cirrhotic patients served as controls. At baseline, 1/22 (4.5%) OLT patients had pulmonary hypertension while 9/22 (41%) developed pulmonary hypertension following volume infusion (p < 0.0001). In contrast, 0/11 controls manifested elevated pulmonary pressures at baseline or following volume challenge. OLT candidates were found to have significant increases in mean pulmonary pressure and capillary wedge pressure (PCWP) compared to controls, suggesting intravascular volume overload or left ventricular dysfunction as potential causes. OLT candidates who manifested volume-dependent pulmonary hypertension (a) had a 2-fold higher baseline PCWP, (b) currently smoked, and (c) had previously undergone portosystemic shunts. Aggregate analysis of EKG, echo and CXR for determination of volume-mediated pulmonary hypertension revealed a sensitivity of 25%, specificity of 75% and a positive predictive value of 40%. Preoperative identification of patients with a predisposition to manifesting elevated pulmonary pressures in the context of rapid volume infusion offers the potential for improved risk stratification and optimized clinical management.

  View details for Web of Science ID A1996WC09400009

  View details for PubMedID 8996773

• Analysis of deaths in patients awaiting heart transplantation: Impact on patient selection criteria HEART Haywood, G. A., Rickenbacher, P. R., Trindade, P. T., Gullestad, L., Jiang, J. P., Schroeder, J. S., Vagelos, R., Oyer, P., Fowler, M. B. 1996; 75 (5): 455-462

  Abstract

  To analyse the clinical characteristics of patients who died on the Stanford heart transplant waiting list and to develop a method for risk stratifying status 2 patients (outpatients).Data were reviewed from all patients over 18 years, excluding retransplants, who were accepted for heart transplantation over an eight year period from 1986 to 1994.548 patients were accepted for heart transplantation; 53 died on the waiting list, and 52 survived on the waiting list for over one year. On multivariate analysis only peak oxygen consumption (peak VO2: 11.7 (SD 2.7) v 15.1 (5.2) ml/kg/min, P = 0.02) and cardiac output (3.97 (1.03) v 4.79 (1.06) litres/min, P = 0.04) were found to be independent prognostic risk factors. Peak VO2 and cardiac index (CI) were then analysed in the last 141 consecutive patients accepted for cardiac transplantation. All deaths and 88% of the deteriorations to status 1 on the waiting list occurred in patients with either a CI < 2.0 or a VO2 < 12. In those with a CI < 2.0 and a VO2 < 12, 38% died or deteriorated to status 1 in the first year on the waiting list. Patients with CI > or = 2.0 and a VO2 > or = 12 all survived throughout follow up. Using a Cox's proportional hazards model with CI and peak VO2 as covariates, tables were constructed predicting the chance of surviving for (a) 60 days and (b) 1 year on the waiting list.These data provide a basis for risk stratification of status 2 patients on the heart transplant waiting list.

  View details for Web of Science ID A1996UK45400010

  View details for PubMedID 8665337

• Transplant candidates with severe left ventricular dysfunction managed with medical treatment: Characteristics and survival JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rickenbacher, P. R., Trindade, P. T., Haywood, G. A., Vagelos, R. H., Schroeder, J. S., Willson, K., Prikazsky, L., Fowler, M. B. 1996; 27 (5): 1192-1197

  Abstract

  This study sought to assess the clinical characteristics and survival of patients with symptomatic heart failure who were referred as potential heart transplant candidates, but were selected for medical management.Patients with severe left ventricular dysfunction referred for heart transplantation may be considered too well to be placed immediately on an active waiting transplant list. The clinical characteristics of this patient group and their survival have not been well defined. These patients represent a unique group that are characterized by comparatively low age and freedom from significant comorbid conditions.We studied 116 consecutive patients with symptomatic heart failure, severe left ventricular dysfunction (left ventricular ejection fraction 20 +/- 7% [mean +/- SD]) and duration of symptoms >1 month referred for heart transplantation, who were acceptable candidates for the procedure but who were not listed for transplantation because of relative clinical stability. These patients were followed up closely on optimal medical therapy. A variety of baseline clinical, hemodynamic and exercise variables were assessed to define this patient group and used to predict cardiac death and requirement later for heart transplantation.During a mean follow-up period of 25.0 +/- 14.8 months (follow-up 99% complete), there were eight cardiac deaths (7%) (seven sudden, one acute myocardial infarction). Only nine patients (8%) were listed for heart transplantation. Actuarial 1- and 4-year cardiac survival rates were 98 +/- 1% and 84 +/- 7% (mean +/- SE), respectively, and freedom from listing for transplantation was 95 +/- 2% and 84 +/- 7% (mean +/- SE), respectively. Patients were mainly in New York Heart Association functional class II or III and had a preserved cardiac index (2.4 liters/min.m2), pulmonary capillary wedge pressure of 16 +/- 9 mm Hg (mean +/- SD) and maximal oxygen consumption of 17.4 +/- 4.3 ml/min per kg (mean +/- SD). By logistic regression analysis, there was no predictor for cardiac death. Longer duration of heart failure (p = 0.013) and mean pulmonary artery (p < 0.05) and pulmonary systolic (p = 0.014) and diastolic (p < 0.05) pressures correlated significantly with listing for heart transplantation by univariate logistic regression. By multivariate logistic regression, only pulmonary artery systolic pressure (p < 0.004) and duration of heart failure (p < 0.015) remained as predictors for need for later transplantation.In the current treatment era, prognosis is favorable in a definable group of transplant candidates despite severe left ventricular dysfunction. This patient group can be identified after intensive medical therapy by stable symptoms, a relatively high maximal oxygen uptake at peak exercise and a preserved cardiac output.

  View details for Web of Science ID A1996UD65100031

  View details for PubMedID 8609341

• MAGNETIC-RESONANCE IMAGING-DERIVED PARAMETER OF PORTAL FLOW PREDICTS VOLUME-MEDIATED PULMONARY-HYPERTENSION IN LIVER-TRANSPLANTATION CANDIDATES 52nd Annual Meeting of the Central-Surgical-Association Kuo, P. C., Alfrey, E. J., Li, K., Vagelos, R., Valantine, H., Garcia, G., Dafoe, D. C. MOSBY-ELSEVIER. 1995: 685–92

  Abstract

  Pulmonary hypertension is a source of perioperative mortality after orthotopic liver transplantation (OLT). The purpose of this study is to (1) characterize the pulmonary hemodynamic response in OLT candidates, and (2) determine whether portal flow index (PFI), a magnetic resonance imaging (MRI)-derived parameter, is a useful predictor of the pulmonary hemodynamic response.Twenty-five consecutive OLT candidates underwent right heart catheterization with pressure measurements at baseline and after infusion of 1 L of crystalloid. MRI, chest roentgenography, electrocardiography, and echocardiography were also performed as routine screening techniques. Sixteen patients in intensive care unit with normal liver function served as controls.After volume infusion, pulmonary hypertension (mean pulmonary artery pressure greater than 25 mm Hg) developed in 9 of 25 OLT candidates with elevations in both pulmonary capillary wedge and mean pulmonary pressures. In contrast, 0 of 16 controls experienced pulmonary hypertension (p < 0.01). Although routine modalities did not predict this hemodynamic response, PFI had a 94% specificity and 78% sensitivity.OLT candidates exhibit volume-induced pulmonary hypertension with responses suggestive of left ventricular dysfunction. The significance of this observation is unknown, but the MRI-derived parameter, PFI, may serve as a screening technique to limit catheterization to a select group of OLT candidates.

  View details for Web of Science ID A1995RY29700016

  View details for PubMedID 7570323

• LIVER-TRANSPLANT CANDIDATES EXHIBIT VOLUME-MEDIATED PULMONARY-HYPERTENSION Kuo, P. C., Vagelos, R. H., Alfrey, E. J., Garcia, G., Dafoe, D. C. WILEY-BLACKWELL. 1994: A124–A124

  View details for Web of Science ID A1994PM55600111

• CARDIAC TRANSPLANTATION - THE STANFORD EXPERIENCE IN THE CYCLOSPORINE ERA JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Sarris, G. E., Moore, K. A., Schroeder, J. S., Hunt, S. A., Fowler, M. B., VALANTINE, H. B., Vagelos, R. H., Billingham, M. E., Oyer, P. E., Stinson, E. B., Reitz, B. A., Shumway, N. E. 1994; 108 (2): 240-252

  Abstract

  We analyzed our experience with 496 patients who underwent primary cardiac transplantation since the introduction of cyclosporine immunosuppression (Dec. 16, 1980, to Jan. 7, 1993). There were 388 male and 108 female patients. Mean recipient age was 40 +/- 16 years (range 0.1 to 70 years, median 44 years). Recipient diagnoses included coronary disease in 188, idiopathic cardiomyopathy in 196, viral cardiomyopathy in 35, and congenital heart disease in 28 patients. Donor age was 25 +/- 10 years (range 1 to 53 years, median 24 years). Graft ischemic time was 148 +/- 57 minutes (range 38 to 495 minutes, median 149 minutes). Operative mortality (hospital death) rate was 7.9% +/- 1.3% (70% confidence intervals). Multivariate logistic regression analysis revealed that (higher) pulmonary vascular resistance and gender (female) were the only independent predictors of hospital death (p < 0.05). Actuarial survival estimates for all patients at 1, 5, and 10 years are 82% +/- 1.7% (83% +/- 1.8% adult, 77% +/- 5.2% pediatric), 61% +/- 2.5% (65% +/- 2.5% adult, 64% +/- 6.6% pediatric), and 41% +/- 3.7% (40% +/- 4% adult, 54% +/- 8.6% pediatric), respectively. For 232 patients treated with triple-drug immunosuppression and induction with OKT3 since 1987, survival estimates at 1 and 5 years are 82% +/- 2.6% and 67% +/- 3.7%, respectively. Causes of death for the entire group were rejection in 29 (14% of deaths), infection in 69 (34%), graft coronary disease in 36 (18%), nonspecific graft failure in 6 (3%), malignancy in 19 (10%), stroke in 6 (3%), pulmonary hypertension in 6 (3%), and other causes in 30 (15%) patients. Actuarial freedom from rejection at 3 months, 1 year, and 5 years was 21% +/- 1.9%, 14% +/- 1.7%, and 7.2% +/- 1.5%, respectively (+/- 1 standard error of the mean). Estimates of freedom from rejection-related death at 1, 5, and 10 years were 96% +/- 1%, 93% +/- 1.4%, and 93% +/- 1.4%, respectively. Actuarial freedom from any infection at 3 months and at 1 and 5 years was 40% +/- 2.3%, 27% +/- 2.1%, and 15% +/- 2.0% and from infection-related death, 95% +/- 1.0%, 93% +/- 1.2%, and 85% +/- 1.9%, respectively. Actuarial freedom from (angiographic or autopsy proved) graft coronary artery disease at 1, 5, and 10 years was 95% +/- 1.2%, 73% +/- 2.7%, and 65% +/- 3.6% and from coronary disease-related death or retransplantation 98% +/- 0.7%, 84% +/- 2.2%, and 66% +/- 4.3%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for Web of Science ID A1994PB11400006

  View details for PubMedID 8041172

• ABNORMALITIES OF PULMONARY-FUNCTION IN PATIENTS WITH CONGESTIVE-HEART-FAILURE, AND REVERSAL WITH IPRATROPIUM BROMIDE AMERICAN JOURNAL OF CARDIOLOGY Kindman, L. A., Vagelos, R. H., Willson, K., PRIKAZKY, L., Fowler, M. 1994; 73 (4): 258-262

  Abstract

  Patients with congestive heart failure (CHF) have baseline restrictive and obstructive abnormalities in pulmonary function. Thus, improvement of respiratory parameters may provide a new method for the treatment of CHF. Ipratropium is an inhaled anticholinergic bronchodilator with no reported cardiac or systemic effect. A pilot study was performed to investigate the acute effects of a 72 micrograms inhaled dose of ipratropium bromide on pulmonary function and pulmonary artery pressures in 18 nonsmokers and 11 smokers with severe (New York Heart Association class 2 or 3), stable CHF who were referred for orthotopic cardiac transplantation. An unmatched group of 10 healthy subjects (5 men and 5 women, mean age 36.8 +/- 1.8 years) were studied with pulmonary function testing alone. Forced expiratory volume in 1 second (FEV1) in 15 of 18 nonsmokers with CHF showed a favorable response with a mean improvement of 5.1% (2.74 +/- 0.20 to 2.89 +/- 0.19 liter after drug treatment; p = 0.0026). Forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) improved by 19% (2.50 +/- 0.25 to 3.09 +/- 0.28 liter/s; p = 0.0013). Eight of 11 smokers with CHF responded with a 9.5% increase in FEV1 (2.32 +/- 0.21 to 2.54 +/- 0.19 liter; p = 0.0006) and a 23.2% increase in FEF25-75 (1.82 +/- 0.38 to 2.37 +/- 0.46 liter/s; p = 0.0029). Pulmonary artery pressures, cardiac output, systemic arterial pressures, and cardiac rate and rhythm were unaffected by administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1994MT45700010

  View details for PubMedID 8296756

• DECREASED CYCLIC-AMP DEGRADATION IN NG-108-15 NEUROBLASTOMA X GLIOMA HYBRID-CELLS AND S49 LYMPHOMA-CELLS CHRONICALLY TREATED WITH DRUGS THAT INHIBIT ADENYLATE-CYCLASE JOURNAL OF NEUROCHEMISTRY Thomas, J. M., Vagelos, R., Hoffman, B. B. 1990; 54 (2): 402-410

  Abstract

  The increase in hormone-stimulated cyclic AMP accumulation observed in a variety of intact cells after chronic pretreatment with drugs that inhibit adenylate cyclase activity has been attributed to an increase in adenylate cyclase activity following withdrawal of the inhibitory drug. In NG 108-15 mouse neuroblastoma X rat glioma hybrid cells (NG cells) chronically treated with the muscarinic cholinergic agonist carbachol, we have found a significant decrease in the apparent degradation rate constant for cyclic AMP, in addition to an increase in the prostaglandin E1 (PGE1)-stimulated cyclic AMP synthesis rate in intact cells. In carbachol-pretreated NG cells that were stimulated with a maximally effective dose of PGE1, and that accumulated steady-state cyclic AMP concentrations fourfold or more higher than in control cells, the apparent rate constant for degradation was about 53% lower than the value for control cells. In carbachol-pretreated cells stimulated with a submaximal dose of PGE1 to yield a steady-state cyclic AMP concentration comparable to control cells, the apparent rate constant was 31% lower than the value for control cells. In S49 mouse lymphoma cells (S49 cells) chronically treated with an analog of the inhibitory agonist somatostatin, the first-order rate constant for cyclic AMP degradation in intact cells following isoproterenol stimulation was 29% lower than the value for control cells. Despite these changes in the kinetics of cyclic AMP degradation in intact NG cells and S49 cells, there was either no change or a minimal change (less than 10%) in phosphodiesterase activities assayed in extracts of cells chronically exposed to inhibitory drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990CJ67000006

  View details for PubMedID 1688917

• Selection of patients for cardiac transplantation. Cardiology clinics Vagelos, R., Fowler, M. B. 1990; 8 (1): 23-38

  Abstract

  In order to appropriately allocate the precious resource of donor organs for cardiac transplantation, one must adequately assess the prognosis of the prospective recipient with or without transplantation. This requires knowledge of the natural history of heart failure as well as those parameters by which it is evaluated. It also requires knowledge of those factors that make patients appropriate versus inappropriate surgical candidates. This article approaches both these necessary areas of patient evaluation.

  View details for PubMedID 2407358

• CELLULAR TOLERANCE TO ADENOSINE RECEPTOR-MEDIATED INHIBITION OF LIPOLYSIS - ALTERED ADENSOINE 3',5'-MONOPHOSPHATE METABOLISM AND PROTEIN-KINASE ACTIVATION ENDOCRINOLOGY Hoffman, B. B., Prokocimer, P., Thomas, J. M., Vagelos, R., Chang, H., Reaven, G. M. 1989; 124 (5): 2434-2442

  Abstract

  Prolonged exposure of many types of cells to drugs or hormones that inhibit the activity of the enzyme adenylate cyclase, such as narcotics and alpha 2-adrenergic agonists, leads to enhanced accumulation of cAMP upon removal of the inhibitory drug. We have found previously that chronic infusion of the adenosine A1 receptor agonist phenylisopropyladenosine (PIA), an inhibitor of adenylate cyclase, into rats leads to enhanced isoproterenol-stimulated cAMP accumulation in adipocytes isolated from these animals. The enhanced cAMP accumulation was associated with an impaired ability of PIA to inhibit lipolysis in these cells. In the present study we have investigated the mechanism of the enhanced cAMP accumulation in adipocytes from PIA-infused rats and the relationship of these changes to the impaired antilipolytic action of the drug. The enhanced isoproterenol-stimulated cAMP accumulation in adipocytes prepared from PIA-infused rats was due to both an increased rate of cAMP synthesis and a decreased rate of cAMP metabolism at high concentrations of cAMP without a change in phosphodiesterase activity. There was heterologous desensitization of the ability of PIA, prostaglandin E1, and nicotinic acid to inhibit cAMP accumulation in the adipocytes from PIA-infused rats; there was an increase in the EC50 of each of these agonists, although maximal inhibition of cAMP accumulation was similar. The relationship between the activation of cAMP-dependent kinase and extent of lipolysis was similar in the two groups of cells. We demonstrated that the explanation for the impaired ability of PIA to decrease the rate of isoproterenol (10(-7) M)-stimulated lipolysis in the cells from the PIA-infused rats was due to the markedly increased concentrations of cAMP in these cells, which led to sufficient activation of the kinase to maintain a high rate of lipolysis even in the presence of PIA. In addition, we found that the changes induced by the PIA infusion were largely reversible over a 2-day period after discontinuing the PIA infusion. These results demonstrate that adipocytes from PIA-infused rats provide an interesting model to investigate the mechanisms of tolerance to inhibitory drugs.

  View details for Web of Science ID A1989U353100054

  View details for PubMedID 2539980