Pathophysiology of exercise heart rate recovery: a comprehensive analysis.

Expanded use of exercise heart rate recovery (HRR) has renewed interest in the pathophysiology of heart rate control. This study uses basic physiologic principles to construct a unique model capable of describing the full time course of sympathetic and parasympathetic activity during HRR. The model is tested in a new study of 22 diverse subjects undergoing both maximal and submaximal treadmill exercise. Based on this analysis, prolongation of HRR involves changes within the sinus node, changes in sympathetic function, in parasympathetic function, and in the central mechanisms regulating autonomic balance. The methods may provide unique insight into alterations in autonomic control in health and disease.

Prognostic value of 12-lead electrocardiogram and peak troponin I level after vascular surgery.

OBJECTIVE: The aim of this investigation was to determine if the presence of ischemic electrocardiographic (ECG) changes in patients undergoing vascular surgery provides incremental prognostic information about the long-term risk of death compared with a single peak troponin level within 48 hours after surgery. METHODS: This was a retrospective analysis of 337 patients undergoing moderate-risk to high-risk vascular surgery at our institution whose ECG and biomarker data were complete. Peak cardiac troponin (cTn) I values that exceeded the upper reference limit (URL) were categorized as low-positive (+), at or exceeding the URL but less than three times the URL, or high-positive (+), at or exceeding three times the URL. ECGs were classified as ischemic or nonischemic. The primary outcome was death at 1 year after the vascular operation. Independent predictors of long-term mortality were determined by Cox proportional hazards regression analysis. RESULTS: The most common vascular problem was an expanding abdominal aortic aneurysm (n=185 [55%]). With regard to cTnI, 53 patients (16%) were classified as high (+) and 82 (24%) as low (+). The ECG in 21 patients (6%) showed evidence of myocardial ischemia. An increase in 1-year mortality of 3% for normal, 11% for low (+), and 17% for high (+) (P<.01) was seen with incremental cTn values. Independent predictors of long-term mortality were age (odds ratio [OR], 1.05, 95% confidence interval [CI], 1.02-1.07; P<.01), stratified troponin (OR, 1.62; 95% CI, 1.25-2.10; P<.01), tissue loss (OR, 3.30; 95% CI, 1.72-6.33; P<.01), stratified Revised Cardiac Risk Index (OR, 1.32; 95% CI, 0.97-1.81; P<.07), and statin use (OR, 0.62; 95% CI, 0.40-0.98; P=.04). The presence of ischemia on ECG was not a predictor of long-term mortality. CONCLUSIONS: In the presence of an elevated cTn I, the ECG is not an independent predictor of long-term mortality after vascular surgery. These results support a strategy of routine surveillance of cTns after vascular surgery for the detection of cardiac events and postoperative risk stratification.

Preoperative coronary artery revascularization and long-term outcomes following abdominal aortic vascular surgery in patients with abnormal myocardial perfusion scans: a subgroup analysis of the coronary artery revascularization prophylaxis trial.

BACKGROUND: Abdominal aortic operations have the highest perioperative cardiac risk. To test the impact of preoperative coronary artery revascularization (PR) in this high-risk subset, a post hoc analysis was performed in patients undergoing aortic surgery within the Coronary Artery Revascularization Prophylaxis (CARP) trial. METHODS: The study cohort was a subset of 109 CARP patients with myocardial ischemia on nuclear imaging randomized to a strategy of PR (N = 52) or no PR (N = 57) before their scheduled abdominal aortic vascular operation. The clinical indications for vascular surgery were an expanding aneurysm (N = 62) or severe claudication (N = 47). The composite end-point of death and nonfatal myocardial infarction (MI) was determined by an intention-to-treat analysis following randomization. RESULTS: The median time (Interquartiles) from randomization to vascular surgery was 56 (40, 81) days in patients assigned to PR and 19 (10, 43) days in patients assigned to no PR (P < 0.001). At 2.7 years following randomization, the probability of remaining free of death and nonfatal MI was 0.65 with PR and 0.55 with no PR [unadjusted P = 0.08, odds ratio = 1.67, 95% confidence interval (0.93, 2.99)]. Using a Cox proportional hazard model, predictors of the composite of death and nonfatal MI (odds ratio; 95% confidence interval) were no PR (1.90; 1.06-3.43; P = 0.03) and anterior ischemia on preoperative imaging (1.79; 0.99-3.23; P = 0.07). CONCLUSIONS: In patients with an abnormal cardiac imaging before abdominal aortic vascular surgery, PR was associated with a reduced risk of death and nonfatal MI while anterior ischemia was an identifier of poor outcome independent of the revascularization status.

Culprit coronary lesions requiring percutaneous coronary intervention after vascular surgery often arise from in-stent restenosis of bare metal stents.

BACKGROUND: The natural history of coronary artery disease (CAD) after vascular surgery is poorly defined. The aim of this study was to determine the temporal change of coronary artery lesions requiring revascularization with a percutaneous coronary intervention (PCI) after elective vascular surgery and to determine the utility of preoperative biomarkers on predicting those patients at risk for new coronary lesions. METHODS: The Coronary Artery Revascularization Prophylaxis Trial tested the long-term survival benefit of coronary artery revascularization before elective vascular surgery. Among randomized patients who subsequently required PCI after surgery, the stenosis of the culprit lesion from the follow-up angiogram was compared with the preoperative vessel stenosis at the identical site on the baseline angiogram. RESULTS: A total of 30 patients underwent PCI for progressive symptoms at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery. Of 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that increased from 17 +/- 6% to 91 +/- 2% (P < 0.01) and 14 (47%) had severe CAD at the culprit site preoperatively (group 2), with a stenosis that increased 89 +/- 2% (P = 0.15). The only biomarker that was an identifier of early coronary artery lesion formation in group 1 compared with group 2 patients was a higher baseline homocysteine level (14.6 +/- 1.4 vs. 10.6 +/- 0.7 mg/dL; P = 0.02). CONCLUSIONS: Culprit coronary artery lesions requiring PCI after an elective vascular operation often arise from in-stent restenosis. Therapies that either stabilize existing plaques or prevent restenosis, particularly among patients with elevated homocysteine levels, have the greatest promise for improving postoperative outcomes.

Perioperative complications after vascular surgery are predicted by the revised cardiac risk index but are not reduced in high-risk subsets with preoperative revascularization.

BACKGROUND: The Revised Cardiac Risk Index (RCRI) is useful for risk stratifying patients before noncardiac operations. Among patients with documented coronary artery disease who undergo vascular surgery, it is unclear whether preoperative revascularization reduces postoperative cardiac complications in high-risk subsets defined by the RCRI. METHODS AND RESULTS: The Coronary Artery Revascularization Prophylaxis Trial was a randomized, controlled trial that tested the long-term benefit of a preoperative coronary artery revascularization before elective vascular surgery. Using preoperative baseline characteristics to determine the RCRI, we tested the benefit of preoperative revascularization on death and nonfatal myocardial infarction in patients with multiple risks. Among 462 patients undergoing vascular surgery, there were 72 complications (15.6%) within 30 days postsurgery, including 15 deaths (3.2%) and 57 nonfatal myocardial infarctions (12.3%). The postoperative risk of death and nonfatal myocardial infarction after surgery increased according to the RCRI (odds ratio, 1.73; 95% CI, 1.26 to 2.38; P<0.001), with a rate of 1.6% in patients with no risk that increased to 23.4% in patients with > or =3 risks. Preoperative revascularization had no influence on the incidence of complications in any risk subset (odds ratio, 0.86; 95% CI, 0.50 to 1.49; P=0.60). Among those individuals with > or =2 risks who also demonstrated ischemia on a preoperative stress-imaging test (N=146), the incidence of events was 23% in patients with and without preoperative revascularization (P=0.95). CONCLUSIONS: The risk of death and nonfatal myocardial infarction is accurately predicted by the RCRI in patients undergoing vascular surgery but is not reduced in any high-risk subset of the RCRI with preoperative coronary artery revascularization.

Usefulness of revascularization of patients with multivessel coronary artery disease before elective vascular surgery for abdominal aortic and peripheral occlusive disease.

The Coronary Artery Revascularization Prophylaxis (CARP) study showed no survival benefit with preoperative coronary artery revascularization before elective vascular surgery. The generalizability of the trial results to all patients with multivessel coronary artery disease (CAD) has been questioned. The objective of this study was to determine the impact of prophylactic coronary revascularization on long-term survival in patients with multivessel CAD. Over a 4-year period, 1,048 patients underwent coronary angiography before vascular surgery during screening into the CARP trial. The cohort was composed of registry (n = 586) and randomized (n = 462) patients, and their survival was determined at 2.5 years after vascular surgery. High-risk coronary anatomy without previous bypass surgery included 2-vessel disease (n = 204 [19.5%]), 3-vessel disease (n = 130 [12.4%]), and left main coronary artery stenosis > or = 50% (n = 48 [4.6%]). By log-rank test, preoperative revascularization was associated with improved survival in patients with a left main coronary artery stenoses (0.84 vs 0.52, p <0.01) but not those with either 2-vessel (0.80 vs 0.79, p = 0.83) or 3-vessel (0.79 vs 0.71, p = 0.15) disease. In conclusion, unprotected left main coronary artery disease was present in 4.6% of patients who underwent coronary angiography before vascular surgery, and this was the only subset of patients showing a benefit with preoperative coronary artery revascularization.

Predictors and outcomes of a perioperative myocardial infarction following elective vascular surgery in patients with documented coronary artery disease: results of the CARP trial.

AIMS: The predictors and outcomes of patients with a peri-operative elevation in cardiac troponin I above the 99th percentile of normal following an elective vascular operation have not been studied in a homogeneous cohort with documented coronary artery disease. METHODS AND RESULTS: The Coronary Artery Revascularization Prophylaxis (CARP) trial was a randomized trial that tested the benefit of coronary artery revascularization prior to vascular surgery. Among 377 randomized patients, core lab samples for peak cardiac troponin I concentrations were monitored following the vascular operation and the blinded results were correlated with outcomes. A peri-operative myocardial infarction (MI), defined by an increase in cardiac troponin I greater than the 99th percentile reference (> or =0.1 microg/L), occurred in 100 patients (26.5%) and the incidence was not dissimilar in patients with and without pre-operative coronary revascularization (24.2 vs. 28.6%; P = 0.32). By logistic regression analysis, predictors of MI (odds risk; 95%CI; P-value) were age >70 (1.84; 1.14-2.98; P = 0.01), abdominal aortic surgery (1.82; 1.09-3.03; P = 0.02), diabetes (1.86; 1.11-3.11; P = 0.02), angina (1.67; 1.03-2.64; P = 0.04), and baseline STT abnormalities (1.62; 1.00-2.6; P = 0.05). At 2.5 years post-surgery, the probability of survival in patients with and without the MI was 0.73 and 0.84, respectively (P = 0.03, log-rank test). Using a Cox proportional hazards regression analysis, a peri-operative MI in diabetic patients was a strong predictor of long-term mortality (hazards ratio: 2.43; 95% CI: 1.31-4.48; P < 0.01). CONCLUSION: Among patients with coronary artery disease who undergo vascular surgery, a peri-operative elevation in cardiac troponin levels is common and in combination with diabetes, is a strong predictor of long-term mortality. These data support the utility of cardiac troponins as a means of stratifying high-risk patients following vascular operations.

Coronary artery bypass grafting is superior to percutaneous coronary intervention in prevention of perioperative myocardial infarctions during subsequent vascular surgery.

BACKGROUND: Among patients in need of coronary revascularization before an elective vascular operation, the value of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in preventing perioperative myocardial infarctions is uncertain. We hypothesized that more complete revascularization would improve outcomes after vascular surgery. METHODS: In this Veterans Affairs Cooperative trial involving 18 medical centers, 222 patients underwent elective vascular surgery after coronary revascularization. The mode of coronary revascularization was selected at each site by the local investigators (CABG in 91 patients and PCI in 131 patients). The vascular surgical indications were similar in both groups. RESULTS: There were 2 deaths in the CABG group (2.2%) and 5 deaths in the PCI group (3.8%; p = 0.497) after the vascular procedure. There were fewer perioperative myocardial infarctions after the vascular operation in CABG patients (6.6%) than in PCI patients (16.8%; p = 0.024), despite more diseased vessels in the CABG group (3.0 +/- 1.3 versus 2.2 +/- 1.4, respectively; p < 0.001). The completeness of revascularization (defined as the number of coronary artery vessels revascularized relative to the total number of vessels with a stenosis > or = 70%) in patients in the CABG and PCI groups was 117% +/- 63% and 81% +/- 57%, respectively (p < 0.001). Hospital length of stay in CABG versus PCI patients was 6 (4, 8) and 7 (4, 10) days, respectively (p = 0.078). CONCLUSIONS: Among patients receiving multivessel coronary artery revascularization as prophylaxis for elective vascular surgery, patients having a CABG had fewer myocardial infarctions and tended to spend less time in the hospital after the vascular operation than patients having a PCI. More complete revascularization accounted for the intergroup differences.

Coronary-artery revascularization before elective major vascular surgery.

BACKGROUND: The benefit of coronary-artery revascularization before elective major vascular surgery is unclear. METHODS: We randomly assigned patients at increased risk for perioperative cardiac complications and clinically significant coronary artery disease to undergo either revascularization or no revascularization before elective major vascular surgery. The primary end point was long-term mortality. RESULTS: Of 5859 patients scheduled for vascular operations at 18 Veterans Affairs medical centers, 510 (9 percent) were eligible for the study and were randomly assigned to either coronary-artery revascularization before surgery or no revascularization before surgery. The indications for a vascular operation were an expanding abdominal aortic aneurysm (33 percent) or arterial occlusive disease of the legs (67 percent). Among the patients assigned to preoperative coronary-artery revascularization, percutaneous coronary intervention was performed in 59 percent, and bypass surgery was performed in 41 percent. The median time from randomization to vascular surgery was 54 days in the revascularization group and 18 days in the group not undergoing revascularization (P<0.001). At 2.7 years after randomization, mortality in the revascularization group was 22 percent and in the no-revascularization group 23 percent (relative risk, 0.98; 95 percent confidence interval, 0.70 to 1.37; P=0.92). Within 30 days after the vascular operation, a postoperative myocardial infarction, defined by elevated troponin levels, occurred in 12 percent of the revascularization group and 14 percent of the no-revascularization group (P=0.37). CONCLUSIONS: Coronary-artery revascularization before elective vascular surgery does not significantly alter the long-term outcome. On the basis of these data, a strategy of coronary-artery revascularization before elective vascular surgery among patients with stable cardiac symptoms cannot be recommended.

Disparate opinions regarding indications for coronary artery revascularization before elective vascular surgery.

Despite consensus guidelines, the optimal strategy for preoperative cardiac risk management among patients scheduled for major noncardiac surgery remains controversial. This study assesses current opinion about the role of preoperative coronary revascularization for patients with coronary artery disease scheduled for elective vascular surgery. Thirty-one practicing cardiologists recruited from 4 different regions reviewed case records, imaging tests, and coronary angiograms of 12 patients with coronary artery disease participating in the Coronary Artery Revascularization Prophylaxis (CARP) trial. The need for preoperative coronary revascularization was determined and results summarized using 3 categories: favoring conservative management, neutral, or recommending revascularization (either by percutaneous intervention or bypass surgery). We found recommendations were frequently disparate and often deviated from published guidelines (40% of the time). The likelihood of discordance between 2 cardiologists was 54%, with a 26% chance that recommendations for revascularization would be directly contradictory. Opinions were more often conservative (43%) or aggressive (40%) than neutral (17%). Similar inconsistency was found as to the preferred method of revascularization, with only 1 patient having complete agreement. Thus, this study reveals substantial differences of opinion among cardiologists across the country about the role of preoperative coronary artery revascularization for patients scheduled for elective vascular operations. Deviations from published guidelines are common, suggesting that current consensus statements need additional data to support their recommendations.

Assessing autonomic function by analysis of heart rate recovery from exercise in healthy subjects.

Although delayed recovery of heart rate (HR) after exercise indicates poor prognosis, the relative role of parasympathetic reactivation versus sympathetic withdrawal in controlling exercise HR recovery remains controversial. Quantifying HR recovery is difficult because the rate of recovery varies with exercise level. This study develops a model of HR recovery applicable to multiple exercise levels simultaneously. Using the Levenberg-Marquardt method for nonlinear models, HR curves for 11 healthy volunteers recovering from 4 different levels of exercise were fit to equations incorporating 1 first-order time constant for parasympathetic reactivation and 1 for sympathetic withdrawal. Results provided time constants for parasympathetic reactivation of 44 +/- 37 seconds and for sympathetic withdrawal of 65 +/- 56 seconds. The model fit the HR recovery curves very closely, explaining 99.7 +/- 0.1% of the variance in the data. In conclusion, this study presents a unique method for quantitatively testing theories on the relative roles of sympathetic withdrawal and parasympathetic reactivation during recovery from exercise. It provides indexes of dynamic sympathetic and parasympathetic functions, with the parasympathetic system having a faster response time. It supports theories of coordinated interaction of parasympathetic reactivation and sympathetic withdrawal during exercise recovery and does not support using simple measures of exercise HR recovery as indexes of vagal function alone.

Comparison of plasma concentrations for two amiodarone products.

BACKGROUND: A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists. OBJECTIVE: To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products. METHODS: A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution. RESULTS: Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 +/- 0.48 vs. 1.19 +/- 0.66 micro g/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 +/- 0.30 vs. 0.96 +/- 0.49 micro g/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product. CONCLUSIONS: This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1-3 months after any change from one product to another.