Lawrence A. Yeatman

Effect of Pravastatin on Outcomes after Cardiac Transplantation

BACKGROUND Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect. METHODS Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients). RESULTS Twelve months after transplantation, the pravastatin group had lower mean (+/- SD) cholesterol levels than the control group (193 +/- 36 vs. 248 +/- 49 mg per deciliter, P < 0.001), less frequent cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P = 0.005), better survival (94 percent vs. 78 percent, P = 0.025), and a lower incidence of coronary vasculopathy in the transplant as determined by angiography and at autopsy (3 vs. 10 patients, P = 0.049). There was no difference between the two groups in the incidence of mild or moderate episodes of cardiac rejection. In a subgroup of study patients, intracoronary ultrasound measurements at base line and one year after transplantation showed less progression in the pravastatin group in maximal intimal thickness (0.11 +/- 0.09 mm, vs. 0.23 +/- 0.16 mm in the control group; P = 0.002) and in the intimal index (0.05 +/- 0.03 vs. 0.10 +/- 0.10, P = 0.031). In a subgroup of patients, the cytotoxicity of natural killer cells was lower in the pravastatin group than in the control group (9.8 percent vs. 22.2 percent specific lysis, P = 0.014). CONCLUSIONS After cardiac transplantation, pravastatin had beneficial effects on cholesterol levels, the incidence of rejection causing hemodynamic compromise, one-year survival, and the incidence of coronary vasculopathy.

Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies.

Purified Fab fragments of ovine digoxin-specific antibodies reversed severe digoxin intoxication in a patient who had taken 22.5 mg of the drug with suicidal intent. Atrioventricular block with extreme bradycardia was temporarily managed by pacing, but progressive, intractable hyperkalemia (serum potassium of 8.7 meq per liter) with increasing pacing threshold and progressive intraventricular conduction delay was controlled only after infusion of 1100 mg of Fab. Sinus rhythm returned 10 minutes after completion of Fab infusion. Within five hours, the serum potassium concentration fell to 4.0 meq per liter. Free digoxin concentrations in serum fell sharply to undetectable levels, whereas total serum digoxin concentration concomitantly increased 12-fold. Renal excretion of digoxin bound to Fab was documented. Reversal of toxicity was not accompanied by hemodynamic instability, and antibodies to sheep Fab fragments were not detected in the patients serum after treatment. Thus, purified digoxin-specific Fab fragments are capable of rapid reversal of advanced digoxin toxicity.

Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model

Positron emission tomography allows noninvasive assessment of myocardial blood flow and metabolism, and may aid in defining the extent and severity of an ischemic injury. This hypothesis was tested by studying, in chronically instrumented dogs, regional blood flow and metabolism during and after a 3 hour balloon occlusion of the left anterior descending coronary artery. The metabolic findings after ischemia were compared with the recovery of regional function over a 4 week period. N-13 ammonia was used as a blood flow tracer, and C-11 palmitic acid and F-18 deoxyglucose as tracers of fatty acid and glucose metabolism, respectively. Regional myocardial function was monitored with ultrasonic crystals implanted subendocardially. Regional function improved most between 24 hours and 1 week after reperfusion, but was still attenuated at 4 weeks. The slow functional recovery was paralleled by sustained metabolic abnormalities, reflected by segmentally delayed clearance of C-11 activity from myocardium and increased uptake of F-18 deoxyglucose. Absence of blood flow and C-11 palmitic acid uptake at 24 hours of reperfusion correlated with extensive necrosis as evidenced by histologic examination. Conversely, uptake of C-11 palmitic acid with delayed C-11 clearance and increased F-18 deoxyglucose accumulation identified reversibly injured tissue that subsequently recovered functionally and revealed little necrosis. Thus, recovery of metabolism after 3 hours of ischemia is slow in canine myocardium and paralleled by slow recovery of function. Metabolic indexes by positron tomography early after reperfusion can identify necrotic and reversibly injured tissue. Positron tomography may therefore aid in defining the extent and prognosis of an ischemic injury in patients undergoing reperfusion during evolving myocardial infarction.

Metabolic and functional recovery of ischemic human myocardium after coronary angioplasty

Although revascularization of hypoperfused but metabolically active human myocardium improves segmental function, the temporal relations among restoration of blood flow, normalization of tissue metabolism and recovery of segmental function have not been determined. To examine the effects of coronary angioplasty on 13 asynergic vascular territories in 12 patients, positron emission tomography and two-dimensional echocardiography were performed before and within 72 h of revascularization. Ten patients underwent late echocardiography (67 +/- 19 days) and eight underwent a late positron emission tomographic study (68 +/- 19 days). The extent and severity of abnormalities of wall motion, perfusion and glucose metabolism were expressed as wall motion scores, perfusion defect scores and perfusion-metabolism mismatch scores. Angioplasty significantly increased mean stenosis cross-sectional area (from 0.95 +/- 0.9 to 2.7 +/- 1.4 mm2) and mean cross-sectional luminal diameter (from 0.9 +/- 0.6 to 1.9 +/- 0.5 mm) (both p less than 0.001). Perfusion defect scores in dependent vascular territories improved early after angioplasty (from 116 +/- 166 to 31 +/- 51, p less than 0.002) with no further improvement on the late follow-up study. The mean perfusion-metabolism mismatch score decreased from 159 +/- 175 to 65 +/- 117 early after angioplasty (p less than 0.01) and to 26 +/- 29 at late follow-up (p less than 0.001 vs. before angioplasty; p = NS vs. early after angioplasty). However, absolute rates of glucose utilization remained elevated early after revascularization, normalizing only at late follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Fractionated endocardial electrograms are associated with slow conduction in humans: evidence from pace-mapping.

Fractionated ventricular electrograms recorded during catheter mapping may arise from areas of asynchronous depolarization associated with slow conduction, the substrate for reentrant ventricular tachycardia, but can also be a nonspecific abnormality or even artifact. To determine whether fractionated sinus rhythm electrograms are associated with slow conduction in humans, the results of endocardial catheter mapping and pacing at 133 endocardial sites in 13 patients were analyzed. Eleven patients had sustained monomorphic ventricular tachycardia and two patients had old myocardial infarction without ventricular tachycardia. Functional evidence of slow conduction at the recording site was assessed by pacing at that site and measuring the interval between the stimulus artifact (S) and the onset of the QRS complex in the 12 lead electrocardiogram (ECG). During pacing at 89 of 90 sites without fractionated sinus rhythm electrograms, the S-QRS interval was less than 40 ms, a value consistent with rapid propagation of the stimulated wave front away from the pacing site. During pacing at 21 (49%) of 43 sites with fractionated sinus rhythm electrograms, the S-QRS interval was greater than 40 ms (range 40 to 140), consistent with slow conduction at the pacing site (p less than 0.001 versus nonfractionated sites). In 9 of the 11 patients with ventricular tachycardia analysis of the paced QRS configuration, electrograms during induced ventricular tachycardia or programmed stimulation during tachycardia suggested that a site with a long S-QRS interval during pacing was located at or near a ventricular tachycardia circuit. Therefore, fractionated sinus rhythm electrograms are often associated with slow conduction, which may be the substrate for reentrant ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Resetting of ventricular tachycardia: Implications for localizing the area of slow conduction

Analysis of local endocardial electrograms recorded during reentrant ventricular tachycardia does not provide direct information as to the participation of the recording site in the tachycardia circuit. To determine if programmed electrical stimulation at the recording site can assist in localizing areas of slow conduction that are participating in the tachycardia circuit, seven patients with sustained monomorphic ventricular tachycardia were studied. The cardiac cycle was scanned with single stimuli delivered during ventricular tachycardia at multiple endocardial sites. In four patients, an endocardial site was identified at which stimuli advanced the tachycardia with marked conduction delay and without alteration of the ventricular activation sequence, as indicated by a lack of change in the configuration of the QRS complex and endocardial electrograms distant from the stimulation site. This finding was seen only during stimulation at sites displaying abnormal electrograms and is consistent with premature depolarization of an area of slow conduction within the tachycardia focus by stimuli delivered at or near that area. Attempted endocardial catheter ablation at or adjacent to these sites in three patients was followed by persistent noninducibility of ventricular tachycardia in one patient, marked modification of the configuration and cycle length of inducible tachycardia in one patient and transient noninducibility of tachycardia in one patient. Programmed electrical stimulation during ventricular tachycardia at sites with abnormal electrograms may provide information about the proximity of the stimulation site to the tachycardia circuit.

Longitudinal study of vascular remodeling in coronary arteries after heart transplantation.

Cross-sectional studies by intravascular ultrasound (IVUS) in heart transplant recipients have suggested that vascular remodeling occurs in coronary arteries years after transplant. However, no reports describe vascular remodeling in the same cohort of patients studied prospectively using morphometric analysis (10 evenly spaced images obtained from a slow pullback from the left anterior descending coronary artery). Morphometric analysis better reflects total vessel anatomy compared with previously reported site (2 to 3 images) analysis. We reviewed 20 patients studied by IVUS at 2 months, 1 year, 2 years, and 3 years after heart transplant.Over time, the coronary artery luminal area decreased from baseline level of 12.0 mm(2) to a 3-year mark of 9.7 mm(2) (p = 0.02). Vessel shrinkage was seen in 16/20 patients. After an initial rise in intimal parameters (maximal intimal thickness, intimal index, and plaque area) from baseline to 1 year, we found a significant decrease in intimal parameters between Year 1 and Year 3 after transplant. For example, plaque area decreased from 2.05 mm(2) at 1 year post-transplant to 1.48 mm(2) by 3 years post-transplant (p = 0.05). In a majority of heart transplant patients, early intimal thickening in the first year post-transplant is accompanied by constrictive remodeling. Over the subsequent 2 years, further constrictive remodeling is seen despite a decrease in intimal area.

Optimizing stent expansion with new stent delivery systems.

OBJECTIVES The purpose of this study was to assess whether the newer stent delivery systems provide a stented lumen cross-sectional area (CSA) that is equal to the delivery balloon nominal dimensions. BACKGROUND First generation stents were often not adequately expanded with their delivery system and frequently required higher pressure or a larger balloon after deployment. Newer stents were designed to optimize expansion with noncompliant, high-pressure balloons provided as the delivery systems. METHODS Intravascular ultrasound (IVUS) was used to evaluate 38 stents in 32 patients after deployment at 14 to 16 atm with their delivery balloon system. Minimum stent lumen CSA and stent minimum lumen diameter (MLD) were measured by IVUS imaging. The manufacturers expected stent diameter was defined as the balloon diameter measured by the company at the maximum pressure used. The manufacturers expected stent area was calculated based on the manufacturers expected stent diameter. RESULTS The MLD (2.5 +/- 0.5 mm) and minimum stent CSA (6.0 +/- 1.7 mm(2)) by IVUS were significantly smaller than the manufacturers expected stent diameter (3.5 +/- 0.4 mm) and area (9.5 +/- 1.9 mm(2)) (p < 0.0001, respectively). The mean MLD by IVUS was 72 +/- 8% of the expected stent diameter, and the mean minimum stent CSA by IVUS was 62 +/- 10% of the expected stent area. CONCLUSIONS Despite moderately high-pressure inflations, the mean minimum stent CSA actually achieved was, on average, only 62% of the manufacturers expected stent area. To optimize stent deployment, these IVUS observations should be considered during coronary artery stenting.

Coronary arterial spasm versus esophageal spasm: Response to ergonovine

In this report we show that coronary arterial and esophageal spasm are sometimes clinically indistinguishable. Pain patterns can be identical, nitroglycerin can bring relief, interval electrocardiograms and exercise electrocardiograms generally disclose no abnormalities, coronary arteriograms may be within normal limits or nearly so, and, importantly, an ergonovine provocative test can provoke esophageal spasm accompanied by pain mistaken for Prinzmetals angina. Accordingly, chest pain in response to the administration of ergonovine is not evidence of coronary arterial spasm without simultaneous arteriographic proof together with changes in the monitoring electrocardiogram. Conversely, gastroenterologists should not expose patients to the risk of ergonovine without prior assurance that the coronary arterial response is normal. Our observations illustrate these points and identify a patient with symptomatic esophageal spasm previously diagnosed as Prinzmetals angina.

Complicated atherosclerotic lesions: A potential cause of ischemic ventricular arrhythmias in cardiac arrest survivors who do not have inducible ventricular tachycardia?

Sudden cardiac death that is not due to acute myocardial infarction may be due to primary ventricular tachycardia or to an arrhythmia secondary to a transient episode of ischemia. The purpose of this study was to determine if the incidence of complicated coronary lesions, which may be a cause of unstable ischemic syndromes, is increased in survivors of an aborted sudden death, especially those without ventricular tachycardia inducible by programmed ventricular stimulation. Nineteen consecutive survivors of an aborted sudden death not due to an acute infarction who underwent coronary angiography and programmed ventricular stimulation within 3 weeks of the event were matched for age, sex, previous infarction, and severity of coronary artery disease with 38 control patients with stable coronary artery disease. There was no difference in the incidence of complicated coronary lesions between the total group of sudden death victims and controls (47% vs 42%). However, 6 of the 11 (64%) sudden death patients who did not have inducible ventricular tachycardia had a complicated lesion as compared to only two of the eight (25%) patients with inducible ventricular tachycardia (p = 0.10). Angiograms identified a complicated lesion or functioning myocardium supplied only by collateral vessels as possible sources of transient ischemia in 73% of noninducible sudden death patients and in 25% of inducible sudden death patients (p = 0.04). Thus coronary angiography in cardiac arrest survivors who do not have inducible ventricular tachycardia often suggests a possible mechanism of transient ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)