Fúlvio Pileggi

The Medicine, Angioplasty or Surgery Study (MASS): A prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses

OBJECTIVES This study sought to evaluate, in a prospective and randomized trial, the relative efficacies of three possible therapeutic strategies for patients with a single severe proximal stenosis of the left anterior descending coronary artery and stable angina. BACKGROUND Although percutaneous transluminal coronary angioplasty and coronary artery bypass surgery are often performed in patients with a single proximal stenosis of the left anterior descending coronary artery, it is unclear whether revascularization offers greater clinical benefit than medical therapy alone. METHODS At a single center, 214 patients with stable angina, normal ventricular function and a proximal stenosis of the left anterior descending coronary artery > 80% were randomly assigned to undergo mammary bypass surgery (n = 70), balloon angioplasty (n = 72) or medical therapy alone (n = 72). Angioplasty had to be considered technically feasible in every case. The predefined primary study end point was the combined incidence of cardiac death, myocardial infarction or refractory angina requiring revascularization. RESULTS At an average follow-up period of 3 years, a primary end point had occurred in only 2 patients (3%) assigned to bypass surgery compared with 17 assigned to angioplasty (24%) and 12 assigned to medical therapy (17%) (p = 0.0002, angioplasty vs. bypass surgery; p = 0.006, bypass surgery vs. medical treatment; p = 0.28, angioplasty vs. medical treatment, all by log-rank test). There was no difference in mortality or infarction rates among the groups. However, no patient allocated to bypass surgery needed revascularization, compared with eight and seven patients assigned, respectively, to coronary angioplasty and medical treatment (p = 0.019). Both revascularization techniques resulted in greater symptomatic relief and a lower incidence of ischemia on the treadmill test; however, all three strategies eventually resulted in the abolition of limiting angina. CONCLUSIONS The more aggressive therapeutic approach with initial bypass surgery for patients with a single severe proximal stenosis of the left anterior descending coronary artery is associated with a lower incidence of medium-term adverse events than coronary angioplasty or medical treatment. However, all three strategies resulted in a similar incidence of death and infarction during an average follow-up period of 3 years. This information should be taken into consideration when physicians and patients make therapeutic choices in this setting.

Coronary Angioplasty Results in Leukocyte and Platelet Activation With Adhesion Molecule Expression: Evidence of Inflammatory Responses in Coronary Angioplasty

OBJECTIVES This study sought to characterize leukocyte and platelet activation and adhesion molecule expression after coronary angioplasty. BACKGROUND Coronary angioplasty can be regarded as a clinical model of postischemic inflammation because this intervention leads to the release of inflammatory mediators as a result of plaque rupture and endothelial injury. METHODS In 13 patients with stable angina (mean [ +/- SEM] age 56.0 +/- 2.4 years, range 44 to 79), blood samples were drawn from the aorta and coronary sinus immediately before and immediately and 15 min after coronary angioplasty. Subsequently, leukocyte and platelet functions were determined. Eleven control patients (57.5 +/- 2.3 years, range 52 to 78) underwent coronary arteriography. RESULTS Coronary arteriography and angioplasty showed no difference in number of leukocytes between the coronary sinus and the aorta. However, 15 min after coronary angioplasty, there was an increase in neutrophil CD18 and CD11b, monocyte CD14 and platelet glycoprotein IIb/IIIa expression and a decrease in neutrophil L-selectin expression (189 +/- 25%, 163 +/- 27%, 158 +/- 35%, 141 +/- 22% and 31 +/- 10%, respectively, p < 0.01). In the control subjects, no change in adhesion molecule expression occurred. Superoxide production and aggregation in ex vivo-stimulated neutrophils collected from the coronary sinus 15 min after coronary angioplasty was significantly decreased compared with that after coronary arteriography (54 +/- 12% vs. 106 +/- 30% and 58 +/- 11% vs. 102 +/- 29%, respectively, p < 0.01). The reduced responses to phorbol ester stimulation may be explained by previous in vivo activation of neutrophils during coronary angioplasty. CONCLUSIONS Coronary angioplasty increases neutrophil, monocyte and platelet adhesion molecule expression and induces a significant decrease in ex vivo-stimulated neutrophil superoxide generation and aggregation. These findings suggest that coronary angioplasty triggers cellular activation with an inflammatory response that could contribute to restenosis.

Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure.

Abstract The mechanism of increased pulmonary wedge pressure and cardiac output after nitric oxide inhalation is not clear. Nitric oxide is rapidly inactivated by hemoglobin before it can produce systemic effects. 3 Thus, selective nitric oxide pulmonary vasodilator effects led to these preliminary results. The hypothesis is that acute reduction in right ventricular afterload caused an acute increment of right ventricular cardiac output. The acute increment of blood return to the impaired left ventricle not associated with reduction in afterload caused the increase in wedge pressure and consequently pulmonary edema. In addition, acute reduction in right ventricular afterload could lead to redistribution of blood volume to pulmonary circulation. The absence of pulmonary edema in these patients in the nitroprusside study reinforces the importance of selective nitric oxide effects in pulmonary circulation.

Vascular free radical release. Ex vivo and in vivo evidence for a flow-dependent endothelial mechanism.

Mechanisms underlying production of vascular free radicals are unclear. We hypothesized that changes in blood flow might serve as a physiological stimulus for endothelial free radical release. Intact isolated aortas from 45 rabbits were perfused with the spin trap alpha-phenyl-N-tert-butylnitrone (PBN, 20 mmol/L) and formed radical adducts detected by electron paramagnetic resonance spectroscopy (EPR). Sequential perfusion at 2, 7.5, and 12 mL/min changed cumulative vascular PBN radical adduct yields, respectively, from 3.2 +/- 0.9 to 4.1 +/- 0.7 (P < .05) and 7.0 +/- 1.5 (P < .005) pmol/mg with endothelium and from 3.6 +/- 1.6 to 3.8 +/- 1.4 and 2.2 +/- 0.8 pmol/mg without endothelium (P = NS). In endothelialized aortas, superoxide dismutase (SOD) completely blocked flow-induced free radical production, whereas inactivated SOD, indomethacin, and the nitric oxide synthetase antagonist nitro-L-arginine methyl ester (L-NAME) had no effect; relaxations to acetylcholine remained unchanged with higher flows. To assess the role of flow on in vivo radical production, femoral arterial plasma levels of the ascorbyl radical, a stable ascorbate oxidation product, were measured by direct EPR in 56 other rabbits. Ascorbyl levels were assessed at baseline (30.2 +/- 0.7 nmol/L) and at peak-induced iliac flow changes. Flow increases from 25% to 100% due to saline injections through an extracorporeal aortic loop induced significant dose-dependent increases in ascorbyl levels (n = 5). In addition, after papaverine bolus injections, flow increased by 114 +/- 8% versus baseline, and ascorbyl levels increased by 5.4 +/- 0.7 nmol/L (n = 31, P < .001); similar results occurred with adenosine, isoproterenol, or hyperemia after 30-second occlusions (P < .05, n = 4 or 5 in each group). Active SOD completely blocked papaverine-induced ascorbyl radical increase, despite preserved flow response (delta ascorbyl = 0.02 +/- 1.6 nmol/L, P = NS); inactivated SOD, catalase, indomethacin, and L-NAME had no effect. Blood flow decreases of 65% to 100% due to phenylephrine or 60-second balloon occlusions were accompanied by an average decrease of 4.4 nmol/L (P < .05) in ascorbyl levels. No change in ascorbyl signal was observed when rabbit blood alone was submitted to in vitro flow increases through a tubing circuit. Thus, increases in blood flow trigger vascular free radical generation; such a response seems to involve endothelium-derived superoxide radicals unrelated to cyclooxygenase or nitric oxide synthetase activities. This mechanism may contribute to explain vascular free radical generation in physiological or pathological circumstances.

Immunohistochemical characterization of infiltrating cells in human chronic chagasic myocarditis: Comparison with myocardial rejection process

Cellular subpopulations that infiltrate the heart in human chronic chagasic myocarditis were defined immunohistochemically in endomyocardial biopsy (EMB) specimens. T cells formed 96.3% of the inflammatory infiltrate, predominantly CD8+ (cytotoxic/ suppressor) T cells. The mean numbers of CD8+ and CD4+ (helper) T cells in the myocarditis were compared to those present in the myocardial rejection process. Mean numbers of CD8+ T cells were similar in both groups of EMB specimens while CD4+ T cell counts, CD4+/CD8+ ratios and CD4+ antigen expression were significantly lower in the chagasic group compared to the myocardial rejection group (P<0.002). The persistent lower number and diminished expression of CD4+ T cells suggest an immunological imbalance in patients with chronic chagasic myocarditis. A possible participation ofTrypanosoma cruzi parasites in the development of such immunological abnormalities is also discussed.

Plasma kinetics of a chylomicron-like emulsion in patients with coronary artery disease

Chylomicron catabolism in the bloodstream consists of lipolysis by lipoprotein lipase and uptake of remnants by the liver. In rats, triglyceride-rich emulsions can mimic chylomicron metabolism. To further validate this model in man, the emulsion was injected intravenously into fasting and into subjects previously fed a test fatty meal. The plasma kinetic curves of the emulsion 3H-triglyceride and 14C-cholesteryl ester were determined. The fractional clearance rate (FCR) of both labels was markedly reduced in the fed subjects (triglycerides: fed = 0.018 +/- 0.007; fasting = 0.105 +/- 0.013 min-1, P < 0.001; cholesteryl ester: fed = 0.016 +/- 0.001; fasting = 0.040 +/- 0.006 min-1; P < 0.05) indicating that the emulsion and chylomicrons generated from the testinal lipid absorption compete for the same catabolic processes, confirming the validity of the method. The emulsion was injected into 11 patients with CAD and into 11 controls. All had plasma cholesterol < 240 and triglycerides < 250 mg/dl. FCR of triglycerides was 5-fold smaller in CAD compared to controls (0.028 +/- 0.004 and 0.141 +/- 0.069 min-1, respectively, P < 0.01). FCR of cholesteryl ester was 4-fold smaller in CAD than in controls (0.015 +/- 0.004 and 0.056 +/- 0.067 min-1 respectively, P < 0.05). These results indicate that both chylomicron lipolysis and remnant removal are diminished in CAD.

The Effect of Red Wine on Experimental Atherosclerosis: Lipid-Independent Protection ~

To assess the effect of red wine on atherosclerosis, New Zealand rabbits were given 1% cholesterol diet for 12 weeks and compared to animals that received the diet plus either red wine or nonalcoholic wine products (NAWP). Diet induced marked increases in total and LDL cholesterol; yet no significant changes in HDL and triglyceride concentrations occurred. In the control group, plaque area was 69 +/- 9% of the aortic surface, while in the wine and NAWP groups it was only 38 +/- 9 and 47 +/- 12%, respectively (P < 0.0001). The average intima/media thickness ratio was 0.60 +/- 0.2 in control animals, 0.14 +/- 0.09 in the wine group, and 0.39 +/- 0.19 in the NAWP group (P < 0.0001). No significant differences were noted in LDL oxidizability among treatments. Thus, both red wine and NAWP can prevent plaque formation in hypercholesterolemic rabbits despite significant increases in LDL. We speculate that anti-platelet effect, blockade of expression of endothelial cell adhesion molecules, and/or NO stimulation by red wine flavonoids are possible explanations.

Current expectations in dynamic cardiomyoplasty

Dynamic cardiomyoplasty has been evaluated in the treatment of severe cardiomyopathies. This report outlines the results of this procedure in 21 patients with dilated or ischemic cardiomyopathy who were in New York Heart Association class III or IV before operation. There were no operative deaths. Patients were followed up for a mean of 17.6 months. Eight patients died during late follow-up, and actuarial survival rates were 73.2% at 1 year and 65.9% at 2 years of follow-up. Functional class improvement was documented in the surviving patients. Furthermore, significant improvement in left ventricular function was demonstrated by radioisotopic angiography and by heart catheterization for more than 2 years after the operation. These studies documented that left ventricular ejection fraction increased as a result of global improvement in regional wall motion. Absence of clinical and hemodynamic improvement after cardiomyoplasty seems to be related to muscle flap ischemic compromise, whereas the patients condition before operation seems to influence the long-term outcome of cardiomyoplasty.

A Technique of Anastomosis of the Right Internal Mammary Artery to the Circumflex Artery and Its Branches

A new technique for direct revascularization of the left circumflex artery and its ventricular branches through anastomosis with the right internal mammary artery (RIMA) was applied in 56 patients. Postoperative angiographic studies in 17 patients showed that positioned behind the aorta, the RIMA can reach the circumflex artery with no tension, allowing adequate distal filling.

PLASMA KINETIC BEHAVIOR IN HYPERLIPIDEMIC SUBJECTS OF A LIPIDIC MICROEMULSION THAT BINDS TO LOW DENSITY LIPOPROTEIN RECEPTORS

It was previously reported that a protein-free microemulsion (LDE) with structure roughly resembling that of the lipid portion of low density lipoprotein (LDL) was presumably taken up by LDL receptors when injected into the bloodstream. In contact with plasma, LDE acquires apolipoproteins (apo) including apo E that would be the ligand for receptor binding. Currently, apo were associated to LDE by incubation with high density lipoprotein (HDL). LDE-apo uptake by mononuclear cells showed a saturation kinetics, with an apparent Km of 13.1 ng protein/mL. LDE-apo is able to displace LDL uptake by mononuclear cells with a Ki of 11.5 ng protein/mL. LDE without apo is, however, unable to displace LDL. The uptake of 14C-HDL is not dislocated by increasing amounts of LDE-apo, indicating that HDL and LDE-apo do not bind to the same receptor sites. In human hyperlipidemias, LDE labeled with 14C-cholesteryl ester behaved kinetically as expected for native LDL. LDE plasma disappearance curve obtained from eight hypercholesterolemic patients was markedly slower than that from 10 control normolipidemic subjects [fractional clearance rate (FCR)=0.02±0.01 and 0.12±0.04 h−1, respectively; P<0.0001]. On the other hand, in four severely hypertriglyceridemic patients, LDE FCR was not significantly different from the controls (0.07±0.03 h−1). These results suggest that LDE can be a useful device to study lipoprotein metabolism.