Randall H. Vagelos

Clinical, Hemodynamic, and Cardiopulmonary Exercise Test Determinants of Survival in Patients Referred for Evaluation of Heart Failure

Despite recent advances in pharmacologic and surgical therapy for patients with chronic heart failure, prognosis for these patients remains poor [1, 2]. Among patients with severe heart failure who do not undergo transplantation, the annual mortality rate can exceed 50% [3]. In patients with less severe forms of heart failure, the annual mortality rate typically ranges from 10% to 20% [4-8]. Mortality rates vary in large part because of the complexity of heart failure and its highly variable clinical course. One of the continuing challenges facing clinicians who manage patients with heart failure is estimating prognosis. Accurate risk stratification is important, both for giving patients information about the outcome of their disease and for appropriately allocating scarce resources for transplantation. Exercise capacity determined by peak ventilatory oxygen uptake (Vo 2) has attracted considerable interest in recent years as a way to help estimate prognosis in chronic heart failure [4-6, 9-12]. Peak Vo 2 has been shown to complement other clinical and invasive markers of disease severity, including ejection fraction, pulmonary capillary wedge pressure, type of heart failure, and cardiac index. Functional impairment has therefore evolved as an important criterion for selecting patients for transplantation. It has been demonstrated that a peak Vo 2 less than 10 mL/kg per minute identifies a group of patients with a particularly poor 1-year prognosis (1-year mortality rate, 24% to 77%) [6, 9, 12, 13]. Conversely, patients in whom the peak Vo 2 is greater than 14 mL/kg per minute have a 1-year survival rate similar to that of patients receiving transplantation (>90%); this suggests that transplantation can be safely deferred in these patients [9]. However, numerous other criteria have also been proposed [11, 13-16]. Previous studies have tended to include small numbers of observed events; have used end points other than death (such as transplantation or change in status for transplant listing); and have been limited by short follow-up (mean, 2 years), resulting in relatively wide CIs in the odds ratios for death rates. Moreover, there have been few integrated approaches to assessing survival (including clinical, exercise, echocardiographic, and hemodynamic data) in the modern era, in which most patients are aggressively treated with angiotensin-converting enzyme inhibitors and survival seems to be improving [6]. Exercise test, ventilatory gas exchange, clinical, and catheterization data have been gathered from patients with severe heart failure at Stanford University over the past 10 years. The high volume of referrals to Stanford over this period has yielded a relatively robust database, including 187 deaths during a mean follow-up of 4 years, with which to address these issues. We sought to determine clinical, hemodynamic, and cardiopulmonary exercise test predictors of survival in patients referred for evaluation of severe heart failure. Methods Patients The study group included 644 ambulatory patients with advanced heart failure who were referred for evaluation at Stanford University between 1986 and 1995 and underwent a valid cardiopulmonary exercise test. The duration of heart failure was at least 1 month, and most of the patients had had one or more hospital admissions for decompensated heart failure. Evaluation included history, cardiovascular examination, and maximal exercise testing with ventilatory gas exchange analysis. Patients who were unable to undergo exercise testing were not included in the study. Standard medical treatment, including digoxin, diuretic agents, and angiotensin-converting enzyme inhibitors, was administered. Many patients were taking warfarin (46%); antiarrhythmic agents (23%); or a -blocker, usually metoprolol (12%). All patients were stabilized clinically before undergoing exercise testing, right-heart catheterization, and echocardiography. Variables from the initial examination that were included in the analysis included age, sex, body surface area, and type of underlying heart disease. Underlying heart disease was coded as ischemic or idiopathic cardiomyopathy. Ischemic cardiomyopathy was defined on the basis of previous myocardial infarction, percutaneous transluminal coronary angioplasty, bypass surgery, or history of significant coronary artery disease by catheterization. All other patients were considered to have idiopathic cardiomyopathy. Exercise Testing Before undergoing exercise testing, all patients provided written informed consent according to a protocol established by the institutional review board at Stanford University. Symptom-limited maximal exercise tests were performed while patients were upright by using an electrically braked bicycle ergometer at a constant cadence of 60 rpm. A continuous ramp protocol was used in which the work rate was increased by 10 W/min. Ventilatory oxygen uptake was measured by using a Medical Graphics Corporation 2001 system (St. Paul, Minnesota). Gas exchange data were obtained breath by breath and were recorded every 30 seconds. Ventilatory oxygen uptake per minute, carbon dioxide production, expiratory volume per minute, and respiratory exchange ratio were calculated online. Peak Vo 2 was defined as the highest VO (2) achieved during exercise. The ventilatory threshold was determined by two experienced reviewers using the V-slope method [17] and was confirmed by ventilatory criteria. Heart rate was recorded continuously by electrocardiography, and blood pressure was recorded at regular intervals throughout the test with a semiautomated recorder (Quinton STBP-680, Quinton Instruments, Seattle, Washington). Other Procedures Right-heart catheterization with measurement of right atrial, pulmonary artery, and pulmonary wedge pressures and calculation of cardiac output done using the Fick method [18] was performed in 63% of patients. Left ventricular ejection fraction was measured with radionuclide or angiographic ventriculography [19] in 74% of the cohort. Left ventricular dimensions and fractional shortening were obtained by using two-dimensional echocardiography in 51% of patients. Follow-up Patients were followed at the Stanford Heart Failure Clinic or by the referring physician. Patient status was determined from medical records, telephone interview of the patient or the patients family, or an information resource research service (IRSC, Fullerton, California) as of December 1995. Twelve patients (1.7%) were lost to follow-up. The analysis was done with death as the end point; transplantation was considered a censored event (removed from the study at the time of transplantation). Statistical Analysis Data are expressed as the mean SD unless otherwise stated. Group differences (survivors compared with nonsurvivors) were compared by using unpaired t-tests. A Cox proportional-hazards model was used to determine the effect of a given independent variable on time to death. The time to event was expressed in days. Predicted peak Vo 2 was determined by using a sex-, age-, weight-, height-, and protocol-specific formula outlined by Wasserman and colleagues [17] and was expressed as a percentage of normal by using the following equation: achieved peak VO2/predicted peak Vo 2 100. Results Baseline Characteristics Descriptive characteristics of the study sample are presented in Table 1. Eighty percent of patients were men. Idiopathic dilated cardiomyopathy was the predominant underlying cause of chronic heart failure (383 patients [59%]). Ischemic heart disease was the underlying cause in 221 patients (34%), and the remaining 40 patients (6%) had other causes. Despite optimal medical treatment, all patients had symptomatic heart failure with a marked decrease in ventricular function as evidenced by a mean ejection fraction of 0.196 0.096, a peak Vo 2 of 16.1 5.7 mL/kg per minute, and echocardiographic data demonstrating ventricular enlargement with decreased fractional shortening. Eighty percent of patients received angiotensin-converting enzyme inhibitors, 76% received digoxin, and 82% received diuretic agents. After initial examination, 225 patients (34.9%) were accepted for transplantation and put on the waiting list, and 419 (51.4%) were rejected because they were too well, were too sick, were too old, or had pulmonary hypertension or other contraindications to transplantation. Table 1. Baseline Clinical Characteristics Survival and Transplantation During the follow-up period of 48.2 28.3 months, 187 patients (29%) died. Actuarial 1-year and 5-year survival rates were 90.5% and 73.4%, respectively. Of the 225 patients listed for heart transplantation, 104 (16.1% of the total cohort) underwent transplantation (34 of the 104 died during follow-up) and 48 (7.5% of the total cohort) died while awaiting transplantation. Of the patients rejected for transplantation, 81 (12.6% of the total cohort) died during follow-up. The 1-year and 5-year survival rates for patients who received transplants were 85% and 68%, respectively. Patients who were listed for and underwent transplantation were similar to those not listed for transplantation in age, body surface area, and cardiac output but had lower ejection fractions (0.164 0.062 compared with 0.203 0.10), lower peak Vo 2 (14.1 5 mL/kg per minute compared with 16.5 6 mL/kg per minute), and greater pulmonary capillary wedge pressure (25.6 8 mm Hg compared with 20.0 7 mm Hg). Determinants of Survival The clinical, hemodynamic, and exercise data of survivors and nonsurvivors are shown in Table 2. All measurements of exercise capacity (peak Vo 2, exercise time, watts achieved, peak heart rate, and Vo 2 expressed as a percentage of the predicted maximum) were higher among survivors than among nonsurvivors (P < 0.001 for each variable). The Vo 2 and heart rate at the ventilatory threshold were also higher among survivors (P = 0.02 for each). Resting heart rate, pulmonary wedge pressure, cardiac index, a

Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure☆

OBJECTIVES 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). BACKGROUND 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.

Screening for Coronary Artery Disease After Mediastinal Irradiation for Hodgkin's Disease

PURPOSE 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 Hodgkins disease. PATIENTS AND METHODS We enrolled 294 outpatients observed at a tertiary care cancer treatment center after mediastinal irradiation doses 35 Gy for Hodgkins 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. RESULTS 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). CONCLUSION 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.

Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 mL/kg/min revisited.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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.

Predictive Value of the Index of Microcirculatory Resistance in Patients With ST-Segment Elevation Myocardial Infarction

OBJECTIVES 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). BACKGROUND 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. METHODS 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. RESULTS 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 <or=32 U (3,128 +/- 1,634 ng/ml vs. 1,201 +/- 911 ng/ml, p = 0.002). The IMR correlated significantly with 3-month echocardiographic wall motion score (WMS) (R = 0.59, p = 0.002) while the other measures of microvascular function did not. The WMS at 3-month follow-up was significantly worse in the group with an IMR >32 U compared with <or=32 U (28 +/- 7 vs. 20 +/- 4, p = 0.001). On multivariate analysis, IMR was the strongest predictor of peak CK and 3-month WMS. The IMR was the only significant predictor of recovery of left ventricular function on the basis of the percent change in WMS (R = 0.50, p < 0.01). CONCLUSIONS Compared to standard measures, IMR appears to be a better predictor of microvascular damage after STEMI, both acutely and in short term follow-up.

Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure ☆

OBJECTIVES 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). BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Simultaneous Assessment of Fractional and Coronary Flow Reserves in Cardiac Transplant Recipients Physiologic Investigation for Transplant Arteriopathy (PITA Study)

Background—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. Methods and Results—In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFR thermo) 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 ≤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 CFR thermo was 2.5±1.2; in 47% of cases, CFR thermo was ≤2.0. In 14%, the FFR was normal (≥0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction. Conclusions—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.

Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension

Background— 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). Methods and Results— By using Stanford Hospitals 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. Conclusions— 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.

Transplant candidates with severe left ventricular dysfunction managed with medical treatment: Characteristics and survival

OBJECTIVES 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. BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Serial exercise testing and prognosis in selected patients considered for cardiac transplantation.

OBJECTIVES 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. BACKGROUND 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. METHODS AND RESULTS 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. CONCLUSION 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.