Robert B. Case

Long-Term Clinical Course of Patients After Termination of Ventricular Tachyarrhythmia by an Implanted Defibrillator

Background—The implanted cardioverter defibrillator (ICD) improves survival in high-risk cardiac patients. This analysis from the MADIT-II trial database examines the long-term clinical course and subsequent mortality risk of patients after termination of life-threatening ventricular tachyarrhythmias by an ICD. Methods and Results—Life-table survival analysis was performed, and proportional hazards regression analysis was used to evaluate the contribution of baseline clinical factors and time-dependent defibrillator therapy to mortality during long-term follow-up. Of 720 patients with an ICD (average follow-up 21 months), 169 patients received 701 antiarrhythmic device therapies for ventricular tachyarrhythmias. Few baseline characteristics distinguished patients who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. The probability of survival for at least 1 year after first therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) was 80%. The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who survived without receiving ICD therapy, with a high frequency of heart failure and late nonsudden cardiac death after first successful ICD therapy for VF. Conclusions—Successful appropriate therapy by an ICD for VT or VF is associated with 80% survival at 1 year after arrhythmia termination. These patients are at increased risk for heart failure and nonsudden cardiac death after device termination of VT or VF and should receive special attention for the prevention and management of progressive left ventricular dysfunction during long-term follow-up.

Thrombogenic Factors and Recurrent Coronary Events

BACKGROUND Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

Sequential Alterations in Myocardial Lactate Metabolism, S-T Segments, and Left Ventricular Function During Angina Induced by Atrial Pacing

Myocardial lactate metabolism was monitored before, during, and after a period of atrial pacing with a continuous automated sampling technic. The electrocardiogram was recorded, and left ventricular function was evaluated by relating left ventricular end-diastolic pressure to left ventricular stroke work. Seventeen of 21 patients with coronary artery disease experienced angina during pacing, and 13 of these showed lactate production by the myocardium during angina. The abnormalities in lactate metabolism developed early in the pacing period, along with S-T segment depression and impairment of left ventricular function, all of which usually occurred before the onset of pain. In the patients with angina, the mean lactate extraction was 14.1% during the control period and —15.1% during the pacing period. Abnormalities in myocardial lactate metabolism have been demonstrated with greater regularity during pacing-induced angina than during angina precipitated by exercise or isoproterenol. This investigation has demonstrated the sequences of changes in lactate metabolism during and after a period of angina and their relation to electrocardiographic and hemodynamic events.

Type A Behavior and Survival after Acute Myocardial Infarction

To ascertain the influence of personality factors on the course of coronary artery disease, we measured Type A behavior in 516 patients within two weeks after an acute myocardial infarction, using the Jenkins Activity Survey questionnaire. Over a follow-up period of one to three years, there was no relation between the Type A score and total mortality, cardiac mortality, time to death for nonsurvivors, left ventricular ejection fraction, or duration of the stay in the coronary care unit. These negative findings were not changed by restricting the analyses to men below 61 years of age or by comparing extreme score categories. The contributions of behavioral, demographic, and cardiac physiologic factors to postinfarction mortality were also evaluated by multivariate survivorship analyses. The physiologic factors were the only ones that contributed a significant and independent mortality risk; the Type A score did not enter the survivorship model (relative risk, 0.8; 95 per cent confidence interval, 0.5 to 1.5). Thus, we found no relation between Type A behavior and the long-term outcome of acute myocardial infarction.

Biochemical aspects of early myocardial ischemia.

Abstract The biochemical disturbances resulting from inadequate coronary blood flow are briefly reviewed. Results of experiments in which the onset of myocardial ischemia was examined by use of a continuous sampling technic are presented. At the point of maximal coronary arteriolar dilatation, a rise in coronary sinus lactate and potassium levels occurred simultaneously, accompanied by a rise in left atrial pressure. The rates of potassium loss and lactate production from ischemic tissue were directly related; the ratio was approximately 1:2 on a molar basis. The total amount of potassium lost by the left ventricle after 7 minutes of ischemia was estimated to be 1.0 per cent of its normal content, and 5.4 per cent after 17 minutes of ischemia. Restoration of coronary flow resulted in potassium uptake, indicating that potassium lost from an ischemic area is replaced quickly in the presence of adequate coronary flow. Electrocardiographic correlation showed that depression of the junction between the QRS complex and the S-T segment appeared simultaneously with the rise in coronary sinus potassium and lactate levels. The junction became progressively more depressed as metabolic evidence of ischemia increased. The flat “ischemic” S-T segment depression was a later feature, appearing only after ischemia had been well established for several minutes. The early electrocardiographic changes seen in these experiments are not currently accepted as evidence of ischemia in clinical practice. A reexamination of electrocardiographic criteria for ischemia in man, with metabolic correlation, seems warranted.

The Effect of Ischemia and Alterations of Heart Rate on Myocardial Potassium Balance in Man

Myocardial electrolyte balance and lactate metabolism were studied in 30 patients before, during, and after a period of atrial pacing utilizing a continuous automated sampling technic with simultaneous electrocardiographic and hemodynamic observations. Eight patients with coronary artery disease who had no symptoms during pacing and four normal subjects demonstrated myocardial potassium loss but no abnormalities in lactate metabolism, the electrocardiogram, and hemodynamics during pacing. Myocardial potassium loss was correlated with increments in heart rate and was followed by potassium uptake during the post-pacing period. Eighteen subjects developed angina during pacing associated with hemodynamic and electrocardiographic abnormalities. This ischemic group showed significantly greater myocardial potassium loss during pacing than the non-ischemic group, and this was closely associated with myocardial lactate production at a ratio of 1 mEq of potassium being lost for each 2 millimoles of lactate produced. Increased acidity of coronary sinus blood also accompanied potassium loss during ischemia. No significant changes were seen in sodium balance in either group during the study.

Temporal Relationships of Myocardial Lactate Metabolism, Left Ventricular Function, and S-T Segment Depression During Angina Precipitated by Exercise

Continuous monitoring of myocardial lactate metabolism and the electrocardiogram in association with an assessment of left ventricular function were carried out in a group of 14 patients before, during, and after a period of supine leg exercise. Of the 12 patients who were shown to have coronary artery disease, seven experienced exertional angina whereas five remained free of pain. Marked increases in arterial and coronary sinus lactate concentrations were observed in all subjects early in exercise although arterial lactate levels were higher in the angina group. In the normal subjects and in the non-angina group, myocardial lactate extraction increased to 36.7 and 28.5%, respectively, during exercise. In the angina group, however, lactate extraction remained abnormal during exercise, increasing to only 8.8%, but in this group only two patients showed myocardial lactate production. Left ventricular end-diastolic pressure was consistently elevated during exertional angina and showed a close temporal relationship to ischemic S-T segments. Left ventricular stroke work was unchanged at these elevated filling pressures indicating impaired left ventricular contractility. While correlation of exertional angina, S-T segment depression, and hemodynamic abnormalities was close, it was not possible to relate these changes to metabolic evidence of ischemia since this was obscured by the elevated arterial lactate concentrations.

The response of canine coronary vascular resistance to local alterations in coronary arterial P CO2.

The effect of hypercapnia on coronary vascular resistance (CVR) was studied in seven open-chest dogs. Coronary blood flow was supplied to the cannulated left main coronary artery from the femoral artery by a precision pump. Coronary arterial Pco, was locally controlled with a small membrane oxygenator in the coronary perfusion circuit. Each Pco, change was made at a constant coronary flow, and CVR was calculated from the ratio of perfusion pressure to flow. Coronary sinus (CS) Pco, and Po, were recorded continuously from blood withdrawn through a CS catheter. Normocapnia (Pco2 = 42.3 ± 2.8 mm Hg) was obtained with a membrane oxygenator gas composition of 95% O2-5% CO2, and hypocapnia was produced with 100% O,-0% CO2. In addition to physiologically normal coronary flow (determined by a CS Po2 of 20-30 mm Hg) relatively high and low flow states were studied. At a normal control CS Po,, a decrease in coronary arterial Pco, from 423 ± 2.8 to 23.8 ± 1.3 mm Hg caused CVR to increase by 84.2%, from 1.27 ± 0.06 to 2.30 ± 0.04 units. Since pH was inversely related to Pco,, the effect on CVR may have been mediated through a pH change. CS Pco, decreased from 65.2 ± 1.9 to 39.4 ± 1.3 mm Hg. Myocardial oxygen consumption was unchanged. Increases in CVR of 74.5, 119.5, and 69.3% occurred during hypocapnia in three additional experiments in which control arterial Po2 was maintained at 52-90 mm Hg. When CS Po2 was greater than 30 mm Hg, the normocapnic CVR was high, and was only minimally increased by hypocapnia. When coronary flow was reduced to an ischemic level there was little response in CVR to hypocapnia. Thus the level of arterial Pco, can have an important effect on CVR independent of changes in O2 consumption. Myocardial Pco2, derived from meta-bolically produced CO2 and contributed to by arterial CO2, may be a major factor in normal control of coronary flow.

Analysis of Left Ventricular Function by Atrial Pacing

With the technique of right atrial pacing, left ventricular function was assessed in 21 normal subjects and in 13 patients with elevated left ventricular filling pressures. Since cardiac output does not change significantly with atrial pacing, the stroke volume decreases as an inverse function of the pacing rate. Stroke volume can thus be varied over a wide range, and by simultaneous measurement of left ventricular end-diastolic pressure, pacing ventricular function curves can be obtained. The calculated average slope for the ventricular function curve relating stroke volume index to left ventricular end-diastolic pressure was steeper in the normal subjects than in the group with elevated left ventricular end-diastolic pressure, but considerable overlap occurred between the groups. However, in individual patients the pacing ventricular function curve appears useful in assessment of the effect of interventions that augment or depress ventricular performance.

The Influence of Changes in Blood Volume on Angina Pectoris A Study of the Effect of Phlebotomy

Angina pectoris was precipitated in 15 patients with coronary artery disease by the technic of right atrial pacing. This was accompanied by hemodynamic evidence of impaired left ventricular function. In eight patients, while pacing was continued, a phlebotomy averaging 276 ml was carried out and in all but one patient angina was relieved and ventricular function returned to normal. Phlebotomy was accompanied by a decline in cardiac index (9.6%) and left ventricular filling pressure, but no change in brachial artery mean pressure, tension-time index, or dp/dt. With reinfusion of blood, angina returned in all but one patient and there was a rise in left ventricular end-diastolic pressure but no change in cardiac index, brachial artery pressure, tension-time index, or dp/dt. In seven patients alterations of blood volume were carried out between three 9-minute periods of atrial pacing and similar observations were obtained. The observations indicate that phlebotomy exerted its beneficial effect through a reduction in left ventricular volume, and it is suggested that this may be the primary mode of action of nitroglycerin.