Myocardial catecholamines following cold cardioplegic arrest during open-heart surgery

Preservation of both right and left ventricular subendocardial and subepicardial muscle was assessed using quantitative polarization microscopy (birefringence measurements) with preservation of myocardial catecholamines measured by fluorescence microscopy in biopsies from 20 consecutive patients who underwent open heart surgery with cold cardioplegic arrest (St. Thomas' Solution). Six of the 7 patients with clinical complications were predicted from the birefringence results. One developed left ventricular deterioration during bypass, two patients right ventricular deterioration, one patient both left and right ventricular deterioration and two patients had poor left ventricular function before bypass. Birefringence measurements were thus reliable in predicting post-operative cardiac outcome. There were no significant changes during the bypass period in the catecholamine scores, even in those patients who had clinical complications. Fluorescence microscopy showed that the "free" myocardial nerve net and the pericoronary nerve plexuses retained their catecholamine stores equally well. This indicated that St. Thomas' cardioplegia preserves myocardial catecholamine stores, depletion of which would remove a potentially important compensatory mechanism in cardiac pump failure. There may however be a temporary blockade in the release of endogenous cardiac catecholamine (noradrenaline) stores from the adrenergic nerve terminals following cold cardioplegic arrest despite myocardial pump failure.     

Ventricular aneurysmectomy and infarctectomy]

During a 22-month period, April 1972 to February 1974, 4 patients underwent ventricular aneurysmectomy at the Karl Bremer and Tygerberg Hospitals for congestive cardiac failure. In addition, 1 patient with an aneurysm and 3 patients with acute myocardial infarcts, ranging from 16 to 28 days postinfarction, underwent emergency surgery for recurrent malignant arrhythmias. The preoperative treatment, cardiac catheterisation data and surgical findings are outlined. The over-all survival rate is 75% for a mean follow-up period of 12,5 months (range 8-22 months). It is concluded that aneurysmectomy, for congestive cardiac failure, and infarctectomy, for life-threatening ventricular arrhythmias, are gratifying and worthwhile procedures.     

Postoperative death in a patient with unrecognized arrhythmogenic right ventricular dysplasia syndrome

Arrhythmogenic right ventricular dysplasia is an inherited disease causing fatty replacement of heart tissue. This disease often presents as T-wave inversion in the anterior leads of the electrocardiogram (ECG) with life-threatening ventricular arrhythmias. In older patients, progressive right and left ventricular failure can develop. This is a case report of postoperative death occurring in a 59-yr-old woman with undiagnosed arrhythmogenic right ventricular dysplasia after hepatic cystectomy. The patient had T-wave inversion in the inferior ECG leads and no history of arrhythmias. During general anesthesia, cardiovascular collapse occurred in the absence of arrhythmias that was unresponsive to resuscitation.     

Perioperative cardiac complications of pulmonary operations in patients with/without coronary stenosis]

It has been suggested that the presence of ischemic heart disease correlates with an increased risk of cardiac infarction and fatal arrhythmia following noncardiac operations. To prevent these complications, coronary arteriographies were performed on 55 patients before pulmonary surgery for the assessment of the risk of perioperative cardiac complications. A coronary artery obstruction, with a 50% or greater reduction in the internal diameter was recognized on 21 patients (Group 1) and the other 34 patients showed no significant coronary stenotic lesions (Group 2). Discriminant analysis revealed that cardiac index (p less than 0.025), blood sugar level (p less than 0.05), hyperlipidemia (p less than 0.05) and postoperative cardiac failure (p less than 0.005) correlated independently with coronary artery stenosis. Postoperative cardiac complications were observed in the form of atrial arrhythmias (11%), ventricular arrhythmias (16%) and ischemic ECG findings (17%) in all cases. The rate of occurrence of these complications were not different between the two groups. However, the need for therapeutic procedures for perioperative circulatory failure (18%) was much greater in group 1 (p less than 0.005). This study supports the merits of preoperative coronary arterial angiography and the estimation of the left ventricular function in reducing pulmonary perioperative risk.     

Prophylaxis of supraventricular and ventricular arrhythmias after coronary artery bypass grafting with low-dose sotalol

BACKGROUND: Supraventricular tachyarrhythmia (SVT) commonly occurs shortly after coronary artery bypass grafting (CABG), but ventricular arrhythmias are less documented. METHODS: On the 1st postoperative day, 206 consecutive eligible patients were prospectively randomized to a sotalol group (80 mg b.i.d.; n = 103) or a control group without beta-blockade or antiarrhythmic drugs (n = 103). RESULTS: The SVT incidence (predominantly atrial fibrillation) accounted for 16% in the sotalol group versus 48% (p < 0.00001). Multivariate analysis showed that sotalol reduced the SVT incidence (p < 0.00001, odds ratio, 0.20; 95% confidence interval, 0.09 to 0.42), whereas a lower preoperative left ventricular ejection fraction (p = 0.019) and older age (p = 0.031) were independent risk factors of SVT occurrence. The Holter electrocardiographic analysis (24 hours) demonstrated that sotalol (32 versus 92; p = 0.031) decreased the median number of ventricular events, mostly isolated premature ventricular beats. Neither ventricular proarrhythmia effect nor "torsades de pointes" were detected. Despite strict hemodynamic-based selection, sotalol had to be discontinued in 8 patients (7.8%), for reasons related to asthma in 3 or cardiac reasons in 5. CONCLUSIONS: Oral low-dose sotalol provided considerable and reliable protection in selected nondepressed cardiac function patients, reducing the occurrence of both supraventricular and ventricular arrhythmias after CABG.     

Short-term morbidity and mortality of implantation of automatic implantable cardioverter-defibrillator

Over the 3-year period from Jan. 1, 1986, through Dec. 31, 1988, we have implanted 101 automatic implantable cardioverter-defibrillators into patients with life-threatening ventricular arrhythmias. There were 82 male patients and 19 female patients. The mean age was 58 years with a range of 25 to 82 years. The indication for implantation was ventricular fibrillation in 89 patients and recurrent ventricular tachycardia in 12 patients. Seventy-seven patients had a history of prior myocardial infarction or coronary artery disease, or both. Eighteen patients had nonischemic cardiomyopathy. One patient had a prolonged QT syndrome and five patients had no evidence of preexisting structural heart disease. The mean injection fraction was 37% +/- 17%. Forty-one of the automatic implantable cardioverter-defibrillator implantations were associated with procedures necessitating cardiopulmonary bypass. The hospital mortality rate was 4% and the morbidity rate was 15%. The only statistical difference between those patients who did and did not have postoperative complications was a history of a prior myocardial infarction (90% versus 54%, p less than 0.05). Twenty percent of patients had new-onset postoperative atrial fibrillation after implantation of the device. Eleven percent of patients had sustained ventricular tachycardia postoperatively. Although there was a trend toward a higher complication/death rate in the patients whose automatic implantable cardioverter-defibrillator was inserted in association with cardiopulmonary bypass (24% versus 15%) and the occurrence of new-onset postoperative atrial fibrillation (27% versus 15%), these findings were not statistically significant. Automatic implantable cardioverter-defibrillator implantation with and without concomitant cardiopulmonary bypass is associated with a clinically important morbidity and mortality rate and development of postoperative arrhythmias.     

The overstated risk of preoperative hypokalemia

To examine the relation between preoperative hypokalemia and frequency of intraoperative arrhythmias, Holter monitoring was employed in 447 patients undergoing major cardiac or vascular operations, the group at greatest risk for life-threatening arrhythmias. Based on serum potassium levels measured immediately before surgery, 57% of patients were normokalemic (greater than or equal to 3.6 mEq/L), 34% hypokalemic (3.1-3.5 mEq/L), and 9% severely hypokalemic (less than or equal to 3.0 mEq/L). No arrhythmia occurred at any time in 63% of patients and minor arrhythmias (premature atrial and occasional premature ventricular contractions) occurred in 16%. Frequent or complex ventricular ectopy appeared before and during operation in 92 patients (21%) but was not related to preoperative potassium level or history of long-term diuretic therapy. Frequent and complex ventricular arrhythmias were more common in patients with a history of long-term digoxin therapy or congestive heart failure. Even among these patients, hypokalemia or diuretic therapy did not increase the incidence or severity of ectopy. These data fail to support the common practice of delaying operation for acute potassium replacement in patients whose preoperative serum potassium is less than normal, even in the presence of cardiovascular disease.     

Is left ventricular venting necessary in open heart surgery?

In this study we intended to clarify the benefits of left ventricular venting by comparing the surgical results and clinical courses of 19 adult patients who underwent open heart procedures with venting and those of 44 adult patients who had open heart procedures without venting. All of the patients of both groups underwent operations for acquired heart diseases. The hospital mortality was 10.5% in the vent group and 2.3% in the no-vent group (NS). None of the deaths occurred due to the postoperative low output syndrome in either group. The incidence of spontaneous defibrillation was not different in the two groups, and no patients required postoperative IABP support in either group. The number of patients who needed catecholamine infusion for longer than 24 hours postoperatively were not statistically different in the two groups, and incidence of ventricular arrhythmias was not different in the two groups. The cardiac index determined 6 hours postoperatively was significantly higher in the no-vent group. The left atrial pressure in the no-vent group did not exceed 10 mmHg during cardiopulmonary bypass, if the central venous pressure was maintained below 7 mmHg. It was suggested that distension of the left ventricle and myocardial injuries do not occur during cardiopulmonary bypass without left ventricular venting, provided the central venous pressure is maintained below 6 or 7 mmHg.     

Heart rate-right ventricular stroke volume relation with myocardial revascularization

Whether increasing pacing frequency in cardiac surgical patients effectively improves right ventricular cardiac index depends on the interrelationships between heart rate, stroke volume index, and end-diastolic volume index. If an inverse relation exists between heart rate and right ventricular volume then the decrease in right ventricular ejection fraction described after bypass may be due, in part, to changes in heart rate. We evaluated the effects of pacing at 80, 95, and 110 beats/min using a thermodilution volumetric catheter in 16 patients undergoing myocardial revascularization. End-diastolic volume index, stroke volume index, and stroke work index were significantly greater after bypass than before bypass, whereas right ventricular ejection fraction remained constant. Before and after bypass, sequentially increasing pacing frequency from 80 to 110 beats/min decreased stroke volume index by 28% to 35% (p less than 0.001), end-diastolic volume index by 12% to 14% (p less than 0.001), and right ventricular ejection fraction by 18% to 24% (p less than 0.001). Right ventricular performance, assessed by comparing the stroke volume index to end-diastolic volume index and stroke work index to end-diastolic volume index relations generated during pacing, was not altered by bypass. We conclude that sequentially increasing heart rate from 80 to 110 beats/min fails to improve stroke volume index and consequently cardiac index before or after cardiac operations. Intraoperatively, in patients with normal left ventricular function, increasing pacing frequency decreases right ventricular ejection fraction due to simultaneous reductions in stroke volume index and end-diastolic volume index.     

Propranolol for Prevention of Postoperative Cardiac Arrhythmias: A Randomized Study

Two hundred twenty-three patients were randomly selected to receive propranolol, 10 mg orally every 6 hours, or to serve as controls after coronary artery bypass grafting. The study began at the time of discharge from the intensive care unit. Patients were ineligible if they had cardiac arrhythmias while in the intensive care unit, low cardiac output requiring catecholamine support, or bradycardia requiring a pacemaker. In the control group, cardiac arrhythmias for which treatment was necessary developed in 31 of 136 patients (23%), atrial fibrillation or flutter in 24 patients (18%), and ventricular arrhythmias in 7 (5%). In the group receiving propranolol, cardiac arrhythmias requiring treatment developed in 9 of 87 patients (10%), atrial fibrillation or flutter in 7 (8%), and ventricular arrhythmias in 2 (2%). The difference in frequency with which cardiac arrhythmias occurred between the two groups is significantly different (p < 0.05).We conclude that propranolol is effective in the prevention of cardiac arrhythmias following coronary artery bypass grafting.     

Arrhythmia prophylaxis using propranolol after coronary artery surgery

Sixty patients undergoing coronary artery bypass grafting operations with cold potassium cardioplegia as the method of myocardial preservation either received low-dose oral propranolol (10 mg every 6 hours; 28 patients) or served as controls (32 patients). The study period began after extubation and ended at the time of hospital discharge. On the fourth postoperative day, 24-hour Holter monitoring was performed to assess additional subtle differences in arrhythmias. The overall incidence of symptomatic postoperative arrhythmias was 31% in the control group: 6 patients (19%) had atrial fibrillation or flutter and 4 patients (12%), ventricular arrhythmias. By contrast, 1 patient (4%) in the propranolol group had atrial fibrillation, and no patient had ventricular arrhythmias. The difference in overall arrhythmia rates between the two groups is significant (p less than 0.025). Twenty-four-hour Holter monitoring demonstrated no additional differences in the frequency of simple or complex atrial or ventricular ectopy between the two groups. We conclude that the incidence of postoperative arrhythmias following coronary artery bypass operation is diminished by the oral administration of prophylactic low-dose propranolol. When compared with our previous study [1], in which the method of myocardial preservation was intermittent aortic cross-clamping and moderate hypothermia, there is no difference in the overall incidence of postoperative arrhythmias.     

Calcium Channel Blockers: An Intraoperative and Postoperative Trial in Women

This study analyzes the effects of intraoperative and postoperative calcium channel blockers on myocardial protection, postoperative arrhythmias, perioperative infarctions, and survival. Thirty-nine women undergoing consecutive coronary artery bypass operations were placed either in a control group (N = 23), in which standard cold potassium cardioplegia was used, or in a verapamil-nifedipine group (N = 16), in which verapamil (1 mg per liter) was added to the standard cardioplegic solution and nifedipine was instituted postoperatively.The verapamil-nifedipine group showed a significant reduction in postoperative levels of creatine phosphokinase (p < 0.05). Levels of aspartate aminotransferase were also reduced (74 IU/L) compared with those for the control group (114 IU/L). In the control group, there were 3 early deaths secondary to abrupt ventricular fibrillation, but no patient in the verapamil-nifedipine group died or had serious early ventricular arrhythmias. Late hemodynamic variables were similar in both groups. We conclude that calcium channel blockers enhance myocardial protection during ischemic arrest and may diminish the incidence of fatal early postoperative ventricular arrhythmias in women undergoing coronary revascularization.     

Importance of preoperative myocardial glycogen levels in human cardiac preservation. Preliminary report.

One hundred seventeen patients undergoing elective coronary bypass were divided into four groups according to prebypass myocardial glycogen levels and the use of potassium chloride cardioplegia. Myocardial glycogen levels were enhanced with a preoperative fat loading diet and overnight glucose loading. The control group (n = 27) which had mean cardiac glycogen levels of 750 mg/100 gm heart weight and no cardioplegia, had a transmural myocardial infarct rate of 14.4%; 35% had severe atrial arrhythmias 65% had severe ventricular arrhythmias, and 31% had severe vasopressor dependence. The group (n = 30) with low cardiac glycogen (736 mg/100 gm) and with potassium chloride cardioplegia had an infarct rate of 6.4%; 6.7% had severe atrial arrhythmias, 18% had severe ventricular arrhythmias, and 16.7% had severe vasopressor dependence. However, the group (n = 26) which had high cardiac glycogen levels (1,208 mg/100 gm) and no cardioplegia had no myocardial infarctions; 3.8% had severe atrial arrhythmias, 27% had severe ventricular arrhythmias, and only 7.8% had severe vasopressor need. The group (n = 34) which had high glycogen levels (1,516 mg/100 gm) and potassium chloride cardioplegia did best of all with no myocardial infarctions or no severe atrial arrhythmias; 14% had severe ventricular arrhythmias and 2.81% severe vasopressor need. The lessening of vasopressor dependence and severe atrial and ventricular arrhythmias were significant by chi square contingency tables at p less than 0.05 and p less than 0.001, respectively. One cardiac-related death each occurred in the two groups with low glycogen and none in those with high glycogen levels. This suggests that better preoperative cardiac nutrition as represented by enhanced cardiac glycogen helps that heart tolerate anoxic stress whether cardioplegia is utilized or not and is additive to potassium chloride cardioplegia.     

Anaesthetic implications of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Arrhythmogenic right ventricular dysplasia, also called right ventricular cardiomyopathy, is a genetically determined heart muscle disease, characterised by life-threatening ventricular arrhythmias in apparently healthy young people. The primary myocardial pathology is that the myocardium of the right ventricular free wall is replaced by fibrous or fibrofatty tissue, with scattered residual myocardial cells. Right ventricular function is abnormal and in severe cases is associated with global right ventricular dilation and overt biventricular heart failure. Although still relatively rare, arrhythmogenic right ventricular cardiomyopathy is a well recognised cause of sudden unexpected peri-operative death. In this review, we describe the basic characteristics of this disease, emphasising the diagnosis and we offer some suggestions for the anaesthetic management of these patients in the peri-operative period.     

Myosin: a highly sensitive indicator of myocardial necrosis after cardiac operations

Plasma levels of ventricular myosin fragments, determined with monoclonal antibodies to myosin heavy chains, were studied in 27 patients after cardiac operations (17 aorta-coronary bypass grafts and 10 valve replacements) to assess their possible role as a marker of perioperative myocardial necrosis. Five patients had perioperative myocardial necrosis after aorta-coronary bypass grafts as indicated by changes in the electrocardiogram and elevated levels of the MB isoenzyme of creatine kinase. Six more patients were also studied after thoracic operations performed by the same sternotomy approach. After cardiac operations, myosin levels increased from postoperative day 3 and reached peak values on day 7. Peak myosin values in patients with perioperative myocardial necrosis after aorta-coronary bypass grafting were significantly higher than in patients after an identical operation but without perioperative myocardial infarction (3793 +/- 592 versus 369 +/- 47 ng/ml; p less than 0.001). These results suggest that plasma myosin is a sensitive marker of myocardial necrosis. Furthermore, peak plasma levels of ventricular myosin after coronary bypass grafting without myocardial infarction (mean value 369 +/- 47 ng/ml) were not significantly different from peak levels after thoracic operations (mean value 253 +/- 52 ng/ml), whereas they were significantly higher after valve replacement (mean value 794 +/- 149 ng/ml; p less than 0.01). These results indicate that a certain degree of myocardial necrosis occurs during value replacement that is undetectable by the usual diagnostic criteria for perioperative myocardial infarction. We conclude that the plasma level of ventricular myosin fragments is a more specific and accurate marker of perioperative myocardial necrosis than changes in the electrocardiogram or elevated creatine kinase MB levels. Therefore the detection of myosin fragments, which appear in the serum on the third day after cardiac operations, may be useful for precise comparisons of different techniques of myocardial protection.     

Modification of supraventricular tachyarrhythmias by stimulating atrial neurons

The effects of stimulating the right atrial ventral ganglionated plexus on ventricular performance during atrial tachycardia was studied in 8 lightly sedated (pentobarbital, 2.5 mg/kg intravenously) dogs with sterile pericarditis. Atrial arrhythmias were induced by electrical stimulation (10 V, 4 ms, 100 Hz) of the right atrium through previously inserted temporary bipolar pacemaker wires. Various types of supraventricular tachycardias were produced. Atrial fibrillation was produced in 3 dogs, atrial tachycardia in all 8 dogs, different atrioventricular nodal ectopic rhythms in 6 dogs, and atrial flutter in 1 dog. These arrhythmias were associated with irregular ventricular contractions that resulted in low ventricular pressures during many cardiac cycles such that low or no aortic pressure was generated. Right atrial ventral ganglionated plexus stimulation induced slowing of ventricular rate so that every ventricular contraction resulted in aortic pressure generation, thus increasing mean aortic pressure. Responses elicited by atrial ganglionated plexus stimulation were eliminated after atropine administration. We conclude that electrical stimulation of the right atrial ventral ganglionated plexus results in slowing of ventricular contractile rate during supraventricular tachycardia, presumably by activating efferent vagal neuronal elements, thereby improving ventricular performance. If applicable in humans, this technique may be of use in management of postoperative atrial arrhythmias after cardiac operations.     

Procedural factors associated with early postoperative arrhythmias after repair of congenital heart defects

OBJECTIVES: Early postoperative arrhythmias frequently are a relevant problem in the early postoperative management after surgical intervention for congenital heart disease. Few data are available indicating risk factors for their occurrence. The hypothesis was tested that factors closely related to the surgical procedure itself were associated with a higher incidence of arrhythmias early in the postoperative course after repair of congenital heart disease. METHODS: All consecutive patients undergoing 1 of 3 well-defined surgical procedures were prospectively evaluated for the occurrence of arrhythmias during the entire postoperative hospital stay by means of continuous electrocardiographic monitoring in the intensive care unit and use of 24-hour Holter monitors. Patients examined were those undergoing transatrial closure of a ventricular septal defect, repair of complete atrioventricular canal, and tetralogy of Fallot. The relation between procedural variables and the occurrence of arrhythmias was independently evaluated for each of these 3 heart defects. RESULTS: Early postoperative arrhythmias occurred in 30% of patients with ventricular septal defect (n = 75), 35% of patients with tetralogy of Fallot (n = 52), and 47% of patients with atrioventricular canal (n = 45). Patients with arrhythmias tended to be younger (significant only in the ventricular septal defect group). In all 3 patient groups, there was a significant correlation between incidence of arrhythmias and longer extracorporeal bypass time (P <.05) and longer aortic crossclamp time (P <.01), as well as with higher maximum postoperative troponin serum levels (P <.01). In patients with atrioventricular canal, there was a significant relation between hemodynamically incomplete surgical results and the occurrence of arrhythmias (P <.01). CONCLUSIONS: The occurrence of early postoperative arrhythmias after repair of congenital heart disease was significantly associated with procedure-related risk factors in each of 3 independent patient groups undergoing well-defined surgical procedures.     

Disorders of cardiac rhythm and conduction after radical correction of tetralogy of Fallot]

The work is based on the results of examination of 78 patients conducted before, in the immediate, and in the late-term periods after the operation (6.5 +/- 5.0 years on the average). Holter's monitoring and bicycle ergometry conducted before the operation revealed rhythm disorders in 55% of patients: complete block of the right limb of the bundle of His in 30, I-III degree atrioventricular block in 9%, supraventricular arrhythmias in 2.5%, ventricular arrhythmias in 5%, and combined arrhythmias in 7.5% of patients. Complete block of the right limb of the bundle of His was discovered in all patients in the late-term postoperative periods, and other types of rhythm disorders were found in 62% of patients: I degree atrioventricular block in 2.5%, bifascicular block in 2.5%, ++tri-fascicular block in 1%, ventricular arrhythmias in 26%, and combined arrhythmias in 30% of patients. The results of the examination showed that: (1) the presence of stable block of the right limb of the bundle of His, bifascicular block, as well as ventricular arrhythmia of I-II gradation after Laun-Wolf does not lead to decrease of myocardial working capacity and contractile function. In contrast, III-IV gradient ventricular arrhythmia is attended by significant diminution of myocardial contractility; (2) the incidence of ventricular arrhythmias grows with increase of the patients' age at the time of the operation and intensification of the degree of initial arterial hypoxemia and the anatomical severity of the anomaly; (3) correction of the anomaly contributes to the disappearance of the preoperative arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

A successful transatrial repair of post-infarction ventricular septal defect]

A 63-year-male underwent successful operation for the ventricular septal perforation (VSP) caused by the inferior myocardial infarction. As the condition was stable, an operation was performed at the 43rd day after onset of myocardial infarction. Exposure was obtained by the opening the right atrium and retracting the tricuspid valve. The defect was in the posterior portion of the ventricular septum and closed using a Dacron patch. His postoperative course was uneventful. Postoperative examinations show no residual shunt. We believe that this approach may offer reduced mortality and morbidity in a selected group of patients with acquired posterior VSP, by avoiding such complications as further trauma to the ventricle, hemorrhage, and arrhythmias.     

Cardiac function in obstructive sleep apnea patients following uvulopalatopharyngoplasty.

Obstructive sleep apnea syndrome (OSAS) is associated with severe cardiac arrhythmias and conduction abnormalities. Cor pulmonale and right-sided heart failure may ensue. Uvulopalatopharyngoplasty (UPPP) is one of several treatment modalities suggested for OSAS. Tracheotomy and CPAP treatment in adult OSAS patients and adenotonsillectomy in children with OSAS were shown to lead to improvement in some cardiac parameters. Cardiac function was prospectively evaluated in 19 OSAS patients before and after UPPP. No significant changes after surgery were noted on electrocardiographic studies. Improvement in global and regional function of both ventricles was seen in 91% of the patients. A trend toward significant elevation in left ventricular ejection fraction and a statistically significant increase in right ventricular ejection fraction were observed (45% +/- 9% to 50% +/- 7% [p = 0.007]). Our results support performance of UPPP in selected OSAS patients for relief of potentially life-threatening cardiac pathologies.