Arthur W. Wallace

Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery

BACKGROUND Perioperative myocardial ischemia is the single most important potentially reversible risk factor for mortality and cardiovascular complications after noncardiac surgery. Although more than 1 million patients have such complications annually, there is no effective preventive therapy. METHODS We performed a randomized, double-blind, placebo-controlled trial to compare the effect of atenolol with that of a placebo on overall survival and cardiovascular morbidity in patients with or at risk for coronary artery disease who were undergoing noncardiac surgery. Atenolol was given intravenously before and immediately after surgery and orally thereafter for the duration of hospitalization. Patients were followed over the subsequent two years. RESULTS A total of 200 patients were enrolled. Ninety-nine were assigned to the atenolol group, and 101 to the placebo group. One hundred ninety-four patients survived to be discharged from the hospital, and 192 of these were followed for two years. Overall mortality after discharge from the hospital was significantly lower among the atenolol-treated patients than among those who were given placebo over the six months following hospital discharge (0 vs. 8 percent, P<0.001), over the first year (3 percent vs. 14 percent, P=0.005), and over two years (10 percent vs. 21 percent, P=0.019). The principal effect was a reduction in deaths from cardiac causes during the first six to eight months. Combined cardiovascular outcomes were similarly reduced among the atenolol-treated patients; event-free survival throughout the two-year study period was 68 percent in the placebo group and 83 percent in the atenolol group (P=0.008). CONCLUSIONS In patients who have or are at risk for coronary artery disease who must undergo noncardiac surgery, treatment with atenolol during hospitalization can reduce mortality and the incidence of cardiovascular complications for as long as two years after surgery.

Prophylactic atenolol reduces postoperative myocardial ischemia

Background Perioperative myocardial ischemia occurs in 20–40% of patients at risk for cardiac complications and is associated with a ninefold increase in risk for perioperative cardiac death, myocardial infarction, or unstable angina, and a twofold long‐term risk. Perioperative atenolol administration reduces the risk of death for as long as 2 yr after surgery. This randomized, placebo‐controlled, double‐blinded trial tested the hypothesis that perioperative atenolol administration reduces the incidence and severity of perioperative myocardial ischemia, potentially explaining the observed reduction in the risk for death. Methods Two‐hundred patients with, or at risk for, coronary artery disease were randomized to two study groups (atenolol and placebo). Monitoring included a preoperative history and physical examination and daily assessment of any adverse events. Twelve‐lead electrocardiography (ECG), three‐lead Holter ECG, and creatinine phosphokinase with myocardial banding (CPK with MB) data were collected 24 h before until 7 days after surgery. Atenolol (0, 5, or 10 mg) or placebo was administered intravenously before induction of anesthesia and every 12 h after operation until the patient could take oral medications. Atenolol (0, 50, or 100 mg) was administered orally once a day as specified by blood pressure and heart rate. Results During the postoperative period, the incidence of myocardial ischemia was significantly reduced in the atenolol group: days 0–2 (atenolol, 17 of 99 patients; placebo, 34 of 101 patients; P = 0.008) and days 0–7 (atenolol, 24 of 99 patients; placebo, 39 of 101 patients; P = 0.029). Patients with episodes of myocardial ischemia were more likely to die in the next 2 yr (P = 0.025). Conclusions Perioperative administration of atenolol for 1 week to patients at high risk for coronary artery disease significantly reduces the incidence of postoperative myocardial ischemia. Reductions in perioperative myocardial ischemia are associated with reductions in the risk for death at 2 yr.

Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery.

Background:Perioperative myocardial ischemia occurs in 20–40% of patients at risk for cardiac morbidity and is associated with a ninefold increase in risk of cardiac morbidity. Methods:In a prospective, double-blinded, clinical trial, we studied 190 patients with or at risk for coronary artery disease in two study groups with a 2:1 ratio (clonidine, n = 125 vs. placebo, n = 65) to test the hypothesis that prophylactic clonidine reduces the incidence of perioperative myocardial ischemia and postoperative death in patients undergoing noncardiac surgery. Clonidine (0.2 mg orally as well as a patch) or placebo (tablet and patch) was administered the night before surgery, and clonidine (0.2 mg orally) or placebo (tablet) was administered on the morning of surgery. The patch or placebo remained on the patient for 4 days and was then removed. Results:The incidence of perioperative myocardial ischemia was significantly reduced with clonidine (intraoperative and postoperative, 18 of 125, 14% vs. placebo, 20 of 65, 31%; P = 0.01). Prophylactic clonidine administration had minimal hemodynamic effects. Clonidine reduced the incidence of postoperative mortality for up to 2 yr (clonidine, 19 of 125 [15%] vs. placebo, 19 of 65 [29%]; relative risk = 0.43 [confidence interval, 0.21–0.89]; P = 0.035). Conclusions:Perioperative administration of clonidine for 4 days to patients at risk for coronary artery disease significantly reduces the incidence of perioperative myocardial ischemia and postoperative death.

Association of the pattern of use of perioperative β-blockade and postoperative mortality.

Background:The 1996 atenolol study provided evidence that perioperative &bgr;-adrenergic receptor blockade (&bgr;-blockade) reduced postsurgical mortality. In 1998, the indications for perioperative &bgr;-blockade were codified as the Perioperative Cardiac Risk Reduction protocol and implemented at the San Francisco Veterans Administration Medical Center, San Francisco, California. The present study analyzed the association of the pattern of use of perioperative &bgr;-blockade with perioperative mortality since introduction of the Perioperative Cardiac Risk Reduction protocol. Methods:Epidemiologic analysis of the operations undertaken since 1996 at the San Francisco Veterans Administration Medical Center was performed. The pattern of use of perioperative &bgr;-blockade was divided into four groups: None, Addition, Withdrawal, and Continuous. Logistic regression, survival analysis, and propensity analysis were performed. Results:A total of 38,779 operations were performed between 1996 and 2008. In patients meeting Perioperative Cardiac Risk Reduction indications for perioperative &bgr;-blockade, Addition is associated with a reduction in 30-day (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.33 to 0.83; P = 0.006) and 1-yr mortality (OR, 0.64; 95%, CI 0.51 to 0.79; P < 0.0001). Continuous is associated with a reduction in 30-day (OR, 0.68; 95% CI, 0.47 to 0.98; P = 0.04) and 1-yr mortality (OR, 0.82; 95% CI, 0.67 to 1.0; P = 0.05). Withdrawal is associated with an increase in 30-day (OR 3.93, 95% CI, 2.57 to 6.01; P less than 0.0001) and 1-yr mortality (OR, 1.96; 95% CI, 1.49 to 2.58; P < 0.0001). Conclusion:Perioperative &bgr;-blockade administered according to the Perioperative Cardiac Risk Reduction protocol is associated with a reduction in 30-day and 1-yr mortality. Perioperative withdrawal of &bgr;-blockers is associated with increased mortality.

First Finite Element Model of the Left Ventricle With Mitral Valve: Insights Into Ischemic Mitral Regurgitation

BACKGROUND Left ventricular remodeling after posterobasal myocardial infarction can lead to ischemic mitral regurgitation. This occurs as a consequence of leaflet tethering due to posterior papillary muscle displacement. METHODS A finite element model of the left ventricle, mitral apparatus, and chordae tendineae was created from magnetic resonance images from a sheep that developed moderate mitral regurgitation after posterobasal myocardial infarction. Each region of the model was characterized by a specific constitutive law that captured the material response when subjected to physiologic pressure loading. RESULTS The model simulation produced a gap between the posterior and anterior leaflets, just above the infarcted posterior papillary muscle, which is indicative of mitral regurgitation. When the stiffness of the infarct region was reduced, this caused the wall to distend and the gap area between the leaflets to increase by 33%. Additionally, the stress in the leaflets increased around the chordal connection points near the gap. CONCLUSIONS The methodology outlined in this work will allow a finite element model of both the left ventricle and mitral valve to be generated using noninvasive techniques.

A Computationally Efficient Formal Optimization of Regional Myocardial Contractility in a Sheep With Left Ventricular Aneurysm

A non-invasive method for estimating regional myocardial contractility in vivo would be of great value in the design and evaluation of new surgical and medical strategies to treat and/or prevent infarction-induced heart failure. As a first step towards developing such a method, an explicit finite element (FE) model-based formal optimization of regional myocardial contractility in a sheep with left ventricular (LV) aneurysm was performed using tagged magnetic resonance (MR) images and cardiac catheterization pressures. From the tagged MR images, 3-dimensional (3D) myocardial strains, LV volumes and geometry for the animal-specific 3D FE model of the LV were calculated, while the LV pressures provided physiological loading conditions. Active material parameters (T(max_B) and T(max_R)) in the non-infarcted myocardium adjacent to the aneurysm (borderzone) and in myocardium remote from the aneurysm were estimated by minimizing the errors between FE model-predicted and measured systolic strains and LV volumes using the successive response surface method for optimization. The significant depression in optimized T(max_B) relative to T(max_R) was confirmed by direct ex vivo force measurements from skinned fiber preparations. The optimized values of T(max_B) and T(max_R) were not overly sensitive to the passive material parameters specified. The computation time of less than 5 hours associated with our proposed method for estimating regional myocardial contractility in vivo makes it a potentially very useful clinical tool.

The effect of ventricular volume reduction surgery in the dilated, poorly contractile left ventricle: a simple finite element analysis.

OBJECTIVES Ventricular volume reduction surgery has been proposed by Batista to improve cardiac function in patients with dilated cardiomyopathy. However, limited clinical data exist to determine the efficacy of this operation. A finite element simulation is therefore used to determine the effect of volume reduction surgery on left ventricular end-systolic elastance, diastolic compliance, stroke work/end-diastolic volume (preload recruitable stroke work), and stroke work/end-diastolic pressure (Starling) relationships. METHODS End-diastole and end-systole were represented by elastic finite element models with different unloaded shapes and nonlinear material properties. End-systolic elastance, diastolic compliance, preload recruitable stroke work, and Starling relationships, as well as energy expenditure per gram of unresected myocardium, were calculated. Two different types of volume reduction surgery (apical and lateral) were simulated at 10% and 20% left ventricular mass reduction. RESULTS Ventricular volume reduction surgery causes diastolic compliance to shift further to the left on the pressure-volume diagram than end-systolic elastance. Volume reduction surgery increases the slope of the preload recruitable stroke work relationship (dilated cardiomyopathy 0.006 J/mL; 20% lateral volume reduction surgery 0.009 J/mL) but decreases the slope of the Starling relationship (dilated cardiomyopathy 0.028 J/mm Hg; 20% lateral volume reduction 0.023 J/mm Hg). For a given amount of resection, lateral volume reduction has a greater effect than apical volume reduction. Ten-percent and 20% lateral volume reduction reduces energy expenditure by 7% and 17%, respectively. CONCLUSION Ventricular volume reduction surgery shifts end-systolic elastance and diastolic compliance to the left on the pressure-volume diagram. The net effect on ventricular function is mixed. Volume reduction surgery increases the slope of preload recruitable stroke work, but increased diastolic compliance causes a small decrease in the Starling relationship (3 mm Hg difference between dilated cardiomyopathy and volume reduction surgery at stroke work = 0.5 J).

Magnetic resonance imaging-based finite element stress analysis after linear repair of left ventricular aneurysm

OBJECTIVE Linear repair of left ventricular aneurysm has been performed with mixed clinical results. By using finite element analysis, this study evaluated the effect of this procedure on end-systolic stress. METHODS Nine sheep underwent myocardial infarction and aneurysm repair with a linear repair (13.4 +/- 2.3 weeks postmyocardial infarction). Satisfactory magnetic resonance imaging examinations were obtained in 6 sheep (6.6 +/- 0.5 weeks postrepair). Finite element models were constructed from in vivo magnetic resonance imaging-based cardiac geometry and postmortem measurement of myofiber helix angles using diffusion tensor magnetic resonance imaging. Material properties were iteratively determined by comparing the finite element model output with systolic tagged magnetic resonance imaging strain measurements. RESULTS At the mid-wall, fiber stress in the border zone decreased by 39% (sham = 32.5 +/- 2.5 kPa, repair = 19.7 +/- 3.6 kPa, P = .001) to the level of remote regions after repair. In the septum, however, border zone fiber stress remained high (sham = 31.3 +/- 5.4 kPa, repair = 23.8 +/- 5.8 kPa, P = .29). Cross-fiber stress at the mid-wall decreased by 41% (sham = 13.0 +/- 1.5 kPa, repair = 7.7 +/- 2.1 kPa, P = .01), but cross-fiber stress in the un-excluded septal infarct was 75% higher in the border zone than remote regions (remote = 5.9 +/- 1.9 kPa, border zone = 10.3 +/- 3.6 kPa, P < .01). However, end-diastolic fiber and cross-fiber stress were not reduced in the remote myocardium after plication. CONCLUSION With the exception of the retained septal infarct, end-systolic stress is reduced in all areas of the left ventricle after infarct plication. Consequently, we expect the primary positive effect of infarct plication to be in the infarct border zone. However, the amount of stress reduction necessary to halt or reverse nonischemic infarct extension in the infarct border zone and eccentric hypertrophy in the remote myocardium is unknown.

Ventricular volume, chamber stiffness, and function after anteroapical aneurysm plication in the sheep ☆ ☆☆ ★

OBJECTIVE The success of left ventricular aneurysm plication depends on how the procedure affects both end-systolic elastance and diastolic compliance and how those changes affect ventricular function (stroke work/end-diastolic volume [PRSW] and stroke volume/end-diastolic pressure [Starling] relationships). METHODS Five male Dorsett sheep were surgically instrumented with coronary artery snares, an inferior vena caval occluder, and an ascending aortic ultrasonic flow probe. One week later an anteroapical myocardial infarction was produced by tightening the coronary snares. Ten weeks after myocardial infarction, the left ventricular aneurysm was plicated. Absolute left ventricular volume was measured by long-axis transdiaphragmatic echocardiography, and relative changes in left ventricular volume were measured with a conductance catheter. End-systolic elastance, diastolic compliance, PRSW, and Starling relationships were measured immediately before myocardial infarction, 10 weeks after myocardial infarction (immediately before plication), and immediately after and 6 weeks after aneurysm plication. RESULTS After plication, end-diastolic and end-systolic left ventricular volumes return to preinfarction values. The slopes of end-systolic elastance, diastolic compliance, and PRSW decrease 10 weeks after myocardial infarction, increase with aneurysm plication, and then decrease 6 weeks after aneurysm plication. The Starling relationship undergoes a downward parallel shift with aneurysm plication. CONCLUSION Aneurysm plication abruptly decreases left ventricular volume and diastolic compliance, increases end-systolic elastance and PRSW, but decreases the Starling relationship. The net effect on left ventricular function is mixed. Furthermore, left ventricular remodeling 6 weeks after aneurysm plication causes left ventricular volume, end-systolic elastance, diastolic compliance, PRSW, and the Starling relationship to return to preplication values.

Perioperative β-blockade: atenolol is associated with reduced mortality when compared to metoprolol.

Background:The Atenolol study of 1996 provided evidence that perioperative &bgr;-blockade reduced postsurgical mortality. In 1998, the indications for perioperative &bgr;-blockade were codified as the Perioperative Cardiac Risk Reduction protocol and implemented at the San Francisco Veterans Affairs Medical Center. The current study tested the following hypothesis: Is there a difference in mortality rates between patients receiving perioperative atenolol and metoprolol? Methods:Epidemiologic analysis of the operations performed at the San Francisco Veterans Affairs Medical Center since 1996 was performed. High-risk inpatients with perioperative &bgr;-blockade were divided into two groups: patients who received perioperative atenolol only and those who received metoprolol only. Patients who switched between the two chronic oral &bgr;-blocker medications were excluded. IV administration of &bgr;-blockers was ignored. Propensity matching analysis was used to correct for population differences in risk factors. Results:There were 38,779 operations performed from 1996 to 2008, with 24,739 inpatient procedures. Based on analysis of inpatient medication use, 3,787 patients received atenolol only (1,011) or metoprolol only (2,776). Thirty-day mortality (atenolol 1% vs. metoprolol 3%, P < 0.0008) and 1-yr mortality (atenolol 7% vs. metoprolol 13%, P < 0.0001) differed between the two &bgr;-blockers. Analysis based on inpatient and outpatient &bgr;-blocker use showed a similar pattern. Propensity matching that corrected for multiple cardiac risk factors found an odds ratio (OR) of 2.1 [95% CI 1.5–2.9], P < 0.0001 for increased 1-yr mortality with metoprolol for inpatient use. Conclusion:Perioperative &bgr;-blockade using atenolol is associated with reduced mortality compared with metoprolol.