Hylton I. Miller

Transfer of Endothelial Progenitor and Bone Marrow Cells Influences Atherosclerotic Plaque Size and Composition in Apolipoprotein E Knockout Mice

Objectives—Recent clinical trials use cell therapy with bone marrow (BM) cells or endothelial progenitor cells (EPCs) for ischemic syndromes. We explored the effect of BM cell– or spleen cell–derived EPC transfer on plaque size and stability markers in the apolipoprotein E knockout (apoE KO) mouse model. Methods and Results—ApoE KO mice aged 10 weeks served as recipients. Labeled BM cells and spleen cell–derived EPCs from age-matched apoE KO mice were injected intravenously to 2 groups of recipient mice each. Additional mice served as controls receiving saline. Both protocols were repeated 3 times at 2 weekly intervals. On killing, plaque size and character were studied, lipid profile analyzed, and serum and aortic cytokines assayed. Spleen cell–derived cells contained a significantly larger number of endothelial cell precursors. Labeled EPCs and BM cells were found abundantly in the spleens, yet also in the lesions of the recipient mice. Aortic sinus lesion size was significantly increased in mice receiving BM cells (n=10) in the EPC-treated group (n=10) compared with controls (n=10; a 54% and a 34% increase in aortic sinus plaque area, respectively). Mice receiving EPCs exhibited plaques with larger lipid cores and thinner fibrous caps and a higher number of infiltrating CD3 cells. RT-PCR analysis of aortas revealed reduced expression of mRNA for interleukin-10 (IL-10) in both cell transfer groups. Higher serum concentrations of IL-6 and monocyte chemoattractant protein-1 were found in sera from BM recipients, whereas lower IL-10 levels were found in mice transfused with spleen-derived EPCs. Conclusions—Transfer of BM cells and EPCs may result in an increase in atherosclerotic lesion size, whereas EPC transfer could also potentially influence plaque stability.

Idiopathic ventricular fibrillation: inducibility and beneficial effects of class I antiarrhythmic agents.

Ventricular fibrillation in patients without recognizable heart disease is uncommon and electrophysiologic data on such patients is limited. Over a 7 year period, five patients (three men and two women, ranging in age from 24 to 52 years) without demonstrable heart disease underwent electrophysiologic studies with pharmacologic drug testing because of single (four patients) or multiple (one patient) documented episodes of ventricular fibrillation. The arrhythmic event was unrelated to myocardial ischemia or infarction, metabolic or electrolyte disturbances, drug toxicity, preexcitation, or prolonged QT syndromes. In all three patients receiving no antiarrhythmic drugs and in two pretreated with amiodarone, a rapid poorly tolerated ventricular tachyarrhythmia requiring cardioversion was induced by programmed ventricular stimulation with up to two extrastimuli. In all instances, addition of either oral quinidine or oral disopyramide prevented the induction of sustained ventricular arrhythmias. All five patients were placed on antiarrhythmic drug regimens found effective during electrophysiologic studies and remained asymptomatic during follow-up periods ranging from 12 to 93 (mean 52) months. We conclude that in the patients with idiopathic ventricular fibrillation in our study: programmed ventricular stimulation reliably replicated the spontaneous arrhythmia, class I antiarrhythmic agents effectively prevented induction of the arrhythmia in the laboratory, and in contrast to the severity of the presenting arrhythmia, a benign clinical course was observed during long-term therapy with class I antiarrhythmic agents.

High Anti-Cytomegalovirus (CMV) IgG Antibody Titer is Associated With Coronary Artery Disease and May Predict Post-Coronary Balloon Angioplasty Restenosis

Recent studies have demonstrated that cytomegalovirus (CMV) DNA was found in atherosclerotic coronary arteries in restenotic lesions, and prior infection with CMV could be a strong independent risk factor for restenosis after coronary atherectomy. We studied the correlation between anti-CMV antibody titer and coronary artery disease. Sixty-five patients (50 men and 15 women) with coronary artery disease were enrolled prospectively. All had symptomatic coronary artery disease with an angiographic documentation of a de novo single coronary lesion. All underwent balloon coronary angioplasty and were followed for 12 months with a thallium perfusion scan 3 months after angioplasty. Patients who had recurrent chest pain and/or a positive thallium scan had another coronary angiography. Blood samples were taken before angiography and 1 and 3 months later. Patients with high anti-CMV titer > or = 1:800 had a higher prevalence of coronary artery disease (p <0.001) than seropositive patients with a lower antibody titer (< or = 1:400); patients with high antibody titer (> or = 1:800) had a higher restenosis rate than seropositive patients with a low antibody titer (< or = 1:400) (p <0.05). High antibody titers against CMV (IgG) may be a strong marker for coronary artery disease, and might predict post-coronary angioplasty restenosis. These findings support the infectious theory of atherosclerosis (especially with prior CMV infection), and also suggest that a chronic immunologic response has a role in atherosclerosis and restenosis.

ROLE OF CYTOKINES IN HEART FAILURE

Heart failure is a complex neurohumoral and inflammatory syndrome. Studies have shown that proinflammatory cytokines (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor) are involved in cardiac depression and in the complex syndrome of heart failure. Understanding the involvement of these cytokines may enable us to reverse cardiac depression and heart failure with the use of monoclonal antibodies directed against specific cytokines that may block the downhill progression of heart failure.

Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): results of the Israeli Study of Early Intervention in Myocardial Infarction.

Alteplase (recombinant tissue-type plasminogen activator (rt-PA)) was infused within four hours of onset of symptoms in 286 patients with acute myocardial infarction. Delayed coronary angiography was performed 72 hours after admission with coronary angioplasty if indicated. Electrocardiographic monitoring was continuous during the first hour of treatment. The sum of the ST segment elevations (sigma ST) was calculated on electrocardiograms recorded at entry and an hour later. ST elevations resolved rapidly within one hour of treatment in 189 patients and persisted in 97 patients. Rapid resolution of ST elevation correlated with angiographic coronary patency as determined by coronary angiography 72 hours after admission. The patients with rapid resolution of sigma ST had significantly smaller infarcts and a better clinical outcome than the patients with persistent ST elevation. sigma ST values at entry and one hour after treatment had no additional independent predictive value. Rapid resolution of ST elevations in patients undergoing thrombolysis with alteplase was associated with a significantly smaller release of creatine kinase, better preservation of left ventricular function, lower morbidity, and less short and long term mortality. Rapid resolution of sigma ST elevation is an efficient indicator of clinical outcome in groups of patients with acute myocardial infarction undergoing thrombolysis with alteplase.

Shoulo thrombolytic therapy be administered in the mobile intensive care unit in patients with evolving myocardial infarction? A pilot study

The growing recognition of the importance of early thrombolysis in evolving myocardial infarction was the basis for the present study, which evaluated the effectiveness, feasibility and safety of prehospital thrombolytic therapy. In a relatively small study, 118 patients were allocated to receive either prehospital treatment with recombinant tissue-type plasminogen activator (rt-PA) in the mobile intensive care unit (group A, 74 patients) or hospital treatment (group B, 44 patients). A total of 120 mg of rt-PA was infused over a period of 6 h. All patients were fully heparinized and underwent radionuclide left ventriculography and coronary angiography during hospitalization. Although group A was treated significantly earlier than group B after onset of symptoms (94 +/- 36 versus 137 +/- 45 min, respectively; p less than 0.001), no significant differences were observed between the groups in 1) extent of myocardial necrosis, 2) global left ventricular ejection fraction at discharge, 3) patency of infarct-related artery, 4) length of hospital stay, and 5) mortality at 60 days. However, a trend to a lower incidence of congestive heart failure at hospital discharge was observed in the prehospital-treated compared with the hospital-treated group (7% versus 16%, respectively; p = NS). No major complications occurred during transportation. It is concluded that myocardial infarction can be accurately diagnosed and thrombolytic therapy initiated relatively safely during the prehospital phase by the mobile intensive care team, thus instituting a beneficial clinical trend in favor of prehospital thrombolysis.

High frequency electrocardiography using an advanced method of signal averaging for non-invasive detection of coronary artery disease in patients with normal conventional electrocardiogram

The ability to detect coronary artery disease (CAD) in patients with normal, conventional electrocardiograms (ECG) was studied using high frequency electrocardiography and an advanced method of signal averaging in three groups of subjects. Group A consisted of ten healthy subjects under the age of 30; Group B of 15 patients with chest pains and normal coronary arteries; and Group C of 20 patients with chest pains and CAD. Four hundred ECG waveforms from leads V3, V4 and V5 were recorded, and the recorded analog data were digitized. The digitized waveforms were averaged using a cross-correlation function which operates in the frequency domain (fast-Fourier transform algorithm). The signals were filtered with a digital band pass filter with 150 and 250 Hz low and high cut-off frequencies, respectively. Zones of reduced amplitude in the envelope of the filtered QRS complex of at least two precordial leads were found more significantly in patients with CAD (75%) than in patients without CAD (12% for Groups A and B, p less than 0.00003). However, no significant difference was found between the voltage over the high frequency QRS complex and that of its envelope between the three groups. It is concluded that the morphology of the high frequency QRS complex as determined by this advanced method of analysis of the signal averaged ECG may be a useful indicator for the presence of CAD in patients with normal conventional ECGs.

Study of the mechanism of ultrasound angioplasty from human thrombi and bovine aorta

Ultrasound angioplasty is a newly developed technology for percutaneous arterial recanalization. Data suggest that ultrasound is particularly effective in ablating fresh thrombi. Arterial walls were found to be resistant to ultrasound ablation. Thrombi, aortic wall segments, and hydroxyproline gelatin were studied in vitro to determine their respective ablation rates. The elasticity of the samples was determined in a force-mode apparatus. The cavitation threshold was determined in an arterial phantom apparatus. Thrombi displayed ablation rates that were > 20 times higher than those of aortic wall samples (591 +/- 82 vs 25 +/- 14 mg/s, p < 0.001). The differences in ablation rates were accompanied by significantly lower elasticities in the thrombus group compared with those in the aortic wall group (0.16 +/- 0.05 vs 312 +/- 37 g/cm2, p < 0.001). Experiments with hydroxyproline gelatin suggest a negative correlation (r = -0.90) between elasticity and ultrasound ablation. Ultrasound ablation of thrombi was evident only above the cavitation threshold. Thus, ultrasound angioplasty has the potential to induce the selective injury required for successful transluminal intervention in the treatment of thrombus-rich lesions.

Transcatheter electrical shock ablation of ventricular tachycardia

Transcatheter shock ablation of ventricular tachycardia was attempted in seven patients who had drug-resistant ventricular tachycardia and in one patient in whom ventricular tachycardia was electrophysiologically induced during therapy with multiple antiarrhythmic drugs. Seven patients had previous myocardial infarction and five of them were high risk candidates for surgical therapy. One patient without organic heart disease had repetitive ventricular tachycardia manifesting two different patterns of left bundle branch block. After endocardial mapping, synchronized unipolar 250 to 300 J shocks (one to six) were delivered between the pole recording the earliest endocardial activity during ventricular tachycardia (40 to 200 ms before the onset of the QRS complex) and a body surface electrode. Immediate complications included severe but reversible cardiogenic shock (one patient), nonclinical ventricular tachycardia (two patients, requiring cardioversion in one), transient atrioventricular and intraventricular conduction disturbances (three patients) and permanent left bundle branch block (one patient). A late complication in one patient, left heart failure, occurred 3 days after delivery of five intracardiac shocks. In two patients, left ventricular ejection fraction markedly decreased and in one of them new ventricular contraction abnormalities appeared. Clinical ventricular tachycardia did not recur in five of the seven post-myocardial infarction patients after 7 to 17 months, and it was not inducible in the four patients undergoing late electrophysiologic study. In the patient with idiopathic ventricular tachycardia, one of the configurational types of ventricular tachycardia recurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and inflammatory effects of dietary l-arginine in patients with intractable angina pectoris

We evaluated the effects of oral L-arginine on the clinical outcome and the inflammatory markers of patients with intractable angina pectoris. Our findings demonstrated a significant clinical improvement in 7 of 10 patients, which was associated with a significant decrease in cell adhesion molecule and proinflammatory cytokine levels. Dietary L-arginine may have clinical beneficial effects in patients with intractable angina pectoris, and may have anti-inflammatory properties.