John S. Schroeder

Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure

Background—The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated. Methods and Results—The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction ≤35%, a QRS ≥130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak &OV0312;o2, &OV0312;e/&OV0312;co2, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak &OV0312;o2, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (P=0.04 and P=0.01, respectively), and LV ejection fraction (P=0.02). CRT patients showed statistically significant improvement in &OV0312;e/&OV0312;co2 (P=0.01), NYHA class (P=0.05), and clinical composite response (P=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores. Conclusions—In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

Intracoronary ultrasound in cardiac transplant recipients. In vivo evidence of "angiographically silent" intimal thickening.

BackgroundAccelerated coronary atherosclerosis is a major factor limiting allograft longevity in cardiac transplant recipients. Histopathology studies have demonstrated the insensitivity of coronary angiography for detecting early atheromatous disease in this patient population. Intracoronary ultrasound is a new imaging techniquse that provides characterization of vessel wall morphology. The purpose of this study was to compare in vivo intracoronary ultrasound with angiography in cardiac transplant recipients. Methods and ResultsThe left anterior descending coronary artery was studied with intracoronary ultrasound in 80 cardiac transplant recipients at the time of routine screening coronary angiography 2 weeks to 13 years after transplantation. A mean and index of intimal thickening were obtained at four coronary sites. Intimal proliferation was classified as minimal, mild, moderate, or severe according to thickness and degree of vessel circumference involved. Twenty patients were studied within 1 month of transplantation and had no angiographic evidence of coronary disease. An intimal layer was visualized by ultrasound in only 13 of these 20 presumably normal hearts. The 60 patients studied 1 year or more after transplantation all had at least minimal intimal thickening. Twenty-one patients (35%) showed minimal or mild, 17 (28%) moderate, and 21 (35%) severe thickening. Forty-two of these 60 patients had angiographically normal coronary arteries, 21 (50%) of whom had either moderate or severe thickening. All 18 patients with angiographic evidence of coronary disease had moderate or severe intimal thickening, but there was no statistically significant difference in intimal thickness or index when compared with the patients with moderate or severe proliferation and normal angiograms (thickness, 0.53±0.35 mm versus 0.64±0.30 mm, p = NS; index, 0.28±0.10 versus 0.34±0.10, p = NS). ConclusionsThe majority of patients 1 or more years after cardiac transplantation have ultrasound evidence of intimal thickening not apparent by angiography. Intracoronary ultrasound offers early detection and quantitation of transplant coronary disease and provides characterization of vessel wall morphology, which may prove to be a prognostic marker of disease.

Hemodynamics in Sleep-Induced Apnea: Studies during Wakefulness and Sleep

Twelve patients with predominantly obstructive type sleep apnea underwent cardiac catheterization, hemodynamic monitoring, and arterial blood gas analysis during wakefulness and sleep. Abnormalities during wakefulness included systemic hypertension in four of 12, exercise-induced mild pulmonary hypertension in five of 12, and alveolar hypoventilation in one. During sleep nine patients had cyclic elevations of arterial pressure with each apneic episode, exceeding 200 mm Hg systolic in three of 12. Pulmonary artery pressures increased in 10 of 12, exceeding 60 mm Hg systolic in five. Marked degrees of hypoxemia (arterial P02, less than 50 mm Hg in eight of 12) and moderate hypercapnia with respiratory acidosis were associated with these hemodynamic changes. Cyclic upper airway obstruction during sleep may result in hypercapnia, acidosis, and pronounced hypoxemia, which can lead to hemodynamic abnormalities during sleep. Sustained pulmonary hypertension and possibly systemic hypertension may follow. Tracheostomy is an effective therapy and is recommended to symptomatic patients who have predominantly obstructive apnea but no relievable anatomic cause of upper airway obstruction.

Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations Main Results of the GUARDIAN Trial

Background—The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis. Methods and Results—A total of 11 590 patients with unstable angina or non–ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, P =0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, P =0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, P =0.03), but the rate of non–Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, P =0.005). There were no increases in clinically serious adverse events. Conclusions—No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.

Sleep-induced apnea syndrome: Prevalence of cardiac arrhythmias and their reversal after tracheostomy☆

Cardiac arrhythmias during wakefulness and sleep in 15 patients with sleep-induced obstructive apnea, and the effect of atropine and tracheostomy on these arrhythmias were studied by continuous overnight Holter electrocardiographic, respiratory and electroencephalographic recordings. Sleep was characterized by marked sinus arrhythmia in 14, extreme sinus bradycardia ( less than 30 beats/minute) in six, asystole of 2.5 to 6.3 seconds in five, second degree atrioventricular (A-V) block in two, and ventricular arrhythmias--complex premature ventricular beats in 10 and ventricular tachycardia in two. Arrhythmias during wakefulness were limited to premature ventricular beats in six. Atropine administration was partially and tracheostomy highly effective in preventing the majority of these arrhythmias during sleep. Marked sinus arrhythmia during sleep is characteristic of the syndrome of obstructive sleep apnea and is frequently accompanied by potentially life-threatening tachy- and bradyarrhythmias. Possible mechanism of production of these arrhythmias, the mode of action of tracheostomy and atropine, and the probable role of similar arrhythmias in the sudden infant death syndrome are discussed.

Provocation of coronary spasm with ergonovine maleate: New test with results in 57 patients undergoing coronary arteriography☆

Ergonovine maleate (Ergotrate) was given to 57 patients undergoing coronary arteriography for investigation of angina occurring at rest or without provocation when routine study showed normal arteries or insufficient occlusive disease to explain their symptoms. This provocative test induced coronary arterial spasm in 13 patients, 10 of whom had definite Prinzmetals angina. The spasm was easily reversed with sublingually administered nitroglycerin. The spasm was occlusive or nearly occlusive in nine patients, and there was associated reproduction of the chest pain and S-T elevation similar to the spontaneous episodes. One patient with Prinzmetals angina had S-T depression rather than elevation in association with the chest pain. The other three patients without Prinzmetals angina had focal narrowing without coronary occlusion, reproduction of the chest pain or electrocardiographic changes. Of the 44 patients who did not demonstrate coronary spasm in response to ergonovine, 29 had normal coronary arteries and 15 had various degrees of atherosclerotic occlusive disease. We conclude that cautious administration of ergonovine maleate during coronary arteriography can be safely used to elicit coronary spasm in some patients who have insufficient fixed occlusive disease to explain their symptoms.

A Preliminary Study of Diltiazem in the Prevention of Coronary Artery Disease in Heart-Transplant Recipients

BACKGROUND Accelerated coronary artery disease is a major cause of late morbidity and mortality among heart-transplant recipients. Because calcium-channel blockers can suppress diet-induced atherosclerosis in laboratory animals, we assessed the efficacy of diltiazem in preventing coronary artery disease in transplanted hearts. METHODS Consecutive eligible cardiac-transplant recipients were randomly assigned to receive diltiazem (n = 52) or no calcium-channel blocker (n = 54). Coronary angiograms obtained early after cardiac transplantation and annually thereafter were used for the visual assessment of the extent of coronary artery disease. The average diameters of identical coronary artery segments were measured on the angiograms obtained at base line and at the first and second follow-up examinations. RESULTS In the 57 patients who had all three angiograms, the average coronary artery diameter (+/- SD) 0.27 decreased in the group that received no calcium-channel blocker from 2.41 +/- 0.27 mm at base line to 2.19 +/- 0.28 mm at one year, and to 2.22 +/- 0.26 mm at two years (P < 0.001 for both years). The average diameter in the diltiazem group changed little from the base-line value of 2.32 +/- 0.22 mm (2.32 +/- 0.27 mm at one year and 2.36 +/- 0.22 mm at two years). The average change in the diameter of the segment differed significantly between the two treatment groups (P < 0.001), and the estimated effect of treatment changed only negligibly after adjustment for other relevant clinical variables. New angiographic evidence of coronary artery disease developed in 14 patients not given calcium-channel blockers, as compared with 5 diltiazem-treated patients (P = 0.082). Coronary stenoses greater than 50 percent of the luminal diameter developed in seven patients not given calcium-channel blockers, as compared with two patients given diltiazem; death due to coronary artery disease or retransplantation occurred in five patients in the group that did not receive calcium-channel blockers and none of those who received diltiazem. CONCLUSIONS Our preliminary results suggest that diltiazem can prevent the usual reduction in the diameter of the coronary artery in cardiac-transplant recipients, but further follow-up will be required to determine whether diltiazem can decrease the long-term incidence of symptomatic coronary artery disease.

Unstable angina pectoris: National cooperative study group to compare surgical and medical therapy: II. In-Hospital experience and initial follow-up results in patients with one, two and three vessel disease

Abstract A prospective randomized study comparing intensive medical therapy with urgent coronary bypass surgery for the acute management of patients with unstable angina pectoris was carried out by nine cooperating medical centers under the auspices of the National Heart, Lung, and Blood Institute. Between 1972 and 1976, a total of 288 patients were entered into the study. All patients had transient S-T or T wave changes, or both, in the electrocardiogram during pain; 90 percent had pain at rest in the hospital, and 76 percent had multivessel coronary disease. The medically and surgically treated patients were comparable with respect to clinical, electrocardiographic and angiographic characteristics and left ventricular function. During the total study period, the hospital mortality rate was 5 percent in the surgical group and 3 percent in the medical group (difference not significant). The rate of in-hospital myocardial infarction was 17 and 8 percent in the respective groups (P In the 1st year after hospital discharge class III or IV angina (New York Heart Association criteria) was more common in medically than in surgically treated patients with one vessel disease (22 percent versus 3 percent, P The results indicate that patients with unstable angina pectoris can be managed acutely with intensive medical therapy, including the administration of propranolol and long-acting nitrates in pharmacologic doses, with adequate control of pain in most patients and no increase in early mortality or myocardial infarction rates. Later, elective surgery can be performed with a low risk and good clinical results if the patients angina fails to respond to intensive medical therapy.

Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis A Post Hoc Analysis of a Randomized, Placebo-Controlled Study

BACKGROUND Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Transplant coronary artery disease: Histopathologic correlations with angiographic morphology

Accelerated coronary artery disease is a major cause of morbidity and mortality among cardiac transplant recipients. Ten patients who died or underwent retransplantation within 2 months of coronary angiography had direct correlation of angiographic (normal discrete lesions, diffuse concentric narrowing) with histologic appearance of coronary arteries. Of the 26 angiographically normal segments, 73% showed mild to moderate fibrous intimal thickening by light microscopy. The remainder had intermediate lesions or atheromatous plaques. Discrete stenoses usually corresponded to lipid-rich intermediate or atheromatous disease. In contrast, angiographically diffuse, concentrically narrowed lesions usually were areas of severe fibrous intimal thickening. Fresh or organizing thrombus was most often associated with discrete lesions and accounted for all complete occlusions. Histologic and angiographic comparisons of the degree of luminal narrowing showed generally good correlation for high grade stenoses. Lesions graded as having less than 25% diameter narrowing were often underestimated angiographically as compared with histologic determinations. Transplant coronary artery disease has a heterogeneous histologic and angiographic appearance, with angiographic underestimation of disease in some patients.