Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries.

BACKGROUND. This study was designed to test the hypothesis that endogenously produced nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries of mongrel dogs. METHODS AND RESULTS. NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation, was administered at 5 mg/kg to 15 dogs after the left anterior descending coronary artery was mechanically injured and narrowed by external constrictors and to nine dogs before endothelial injury of the femoral artery and after injury and moderate arterial constriction. Treatment with L-NMMA resulted in cyclic flow variations (as detected by external Doppler flow probes) in the left anterior descending artery of seven of 15 dogs and in the femoral artery of four of nine dogs after endothelial injury. L-Arginine, the precursor for nitric oxide synthesis, was administered at 60 mg/kg and abolished cyclic flow variations in each of the 11 dogs. D-Arginine did not change the L-NMMA-induced cyclic flow variations. Saline infusion did not induce or change cyclic flow variations in any of the animals. Acetylcholine (1, 10, and 100 micrograms/min; n = 9) was administered in the femoral artery of nine additional dogs before and after endothelial injury in moderately stenosed femoral arteries. Acetylcholine did not induce cyclic flow variations in any animal; however, it did increase the severity of cyclic flow variations that developed in severely stenosed arteries. The diameter of the femoral artery was measured by intravascular ultrasound imaging. L-NMMA caused vasoconstriction of normal arteries, but no change was detected in endothelium-injured arteries. In contrast, L-arginine caused vasodilation of normal arteries, but, again, no change was noted in endothelium-injured arteries. Acetylcholine dilated normal femoral arteries but constricted arteries with endothelial injury. In both in vitro and ex vivo platelet studies, L-NMMA enhanced platelet aggregation, whereas L-arginine significantly reduced platelet aggregation. D-Arginine and acetylcholine showed no effect on platelet aggregation. CONCLUSIONS. Promotion of nitric oxide production decreases platelet aggregation and may eliminate cyclic flow variations, whereas a reduction in nitric oxide formation enhances platelet aggregation and may induce cyclic flow variations. Acetylcholine causes vasoconstriction at the femoral arterial site of endothelial injury and may increase the severity of cyclic flow variations.     

Intracardiac Versus Transesophageal Echocardiographic Guidance for Left Atrial Appendage Occlusion: The LAAO Italian Multicenter Registry

Objectives

This study sought to evaluate the feasibility, safety, and efficacy of intracardiac echocardiography (ICE)–guided versus transesophageal echocardiography (TEE)–guided left atrial appendage occlusion (LAAO) by the use of Amplatzer Cardiac Plug or Amulet devices included in a large Italian registry.

Reduction in infarct size by the phospholipase inhibitor quinacrine in dogs with coronary artery occlusion

It has been suggested that activation of tissue phospholipases may contribute to the development of ischemic cell injury. In the present study we sought to assess whether administration of the phospholipase inhibitor quinacrine would reduce the extent of myocardial necrosis after coronary artery occlusion. In open-chest, anesthetized dogs the left anterior descending coronary artery was ligated, and technetium-99-labeled albumin microspheres were injected into the left atrium to measure the area at risk. The animals were then randomly divided into a control group (n = 8) and a group receiving quinacrine (5 mg/kg intravenous bolus followed by a 40 micrograms/kg/min infusion for 6 hours; n = 9). The animals were killed 6 hours after occlusion, and the infarcted area was delineated by triphenyltetrazolium chloride staining. The extent of the risk region was similar in the two groups (32.3 +/- 2.1% of the left ventricle in control dogs and 34.2 +/- 3.4% in quinacrine-treated dogs). Infarct size was 86.4 +/- 8.8% of the risk region in control animals, whereas in treated dogs it averaged 62.3 +/- 6.4% of the risk region (p = 0.05). No differences were found in heart rate, arterial pressure, and rate-pressure product between the two groups. Thus administration of the phospholipase inhibitor quinacrine reduced the extent of myocardial necrosis in a model of fixed coronary artery occlusion. Preservation of membrane phospholipids, reduced formation of lipoxygenase metabolites, or both may mediate this phenomenon.     

Massive chronic atrial thrombosis

We report herein a patient in whom a very large and old thrombus in the left atrium was detected by transesophageal echocardiography. The patient started warfarin and aspirin. After 2 years of therapy, transesophageal echocardiography showed the complete resolution of thrombus in the absence of clinical evidence of embolism. This case indicates that large and presumably organized thrombi may be dissolved by an anticoagulant therapy, although the lytic activity of warfarin has never been demonstrated. Transesophageal echocardiography helps in the identification and follow-up of such conditions and contributes to understanding of warfarin action in left atrial thrombosis.     

Role of new antiplatelet agents as adjunctive therapies in thrombolysis

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.     

The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon during coronary occlusion-reperfusion

The goal of this study was to determine the effects of acute hypercholesterolemia on the evolution of myocardial infarction in a preparation of coronary occlusion-reperfusion. New Zealand white rabbits were fed a 2% cholesterol-enriched diet for 3 days (plasma cholesterol 329 +/- 70 mg/dl), or maintained on the control diet (plasma cholesterol 67 +/- 12 mg/dl). Temporary (30 min) coronary artery occlusion was performed in open-chest rabbits with a suture snare. The snare was released to permit reperfusion. When the animals were killed 5.5 hr later, left ventricles were cut into 3 mm slices. Infarct size was determined by planimetry of tetrazolium-stained slices while the area at risk of infarction (hypoperfused zone) was determined by planimetry of the "cold spots" on autoradiograms of the slices that contained 99m Tc-labeled microspheres that had been injected 1 min after occlusion. Infarct size, expressed as percent of the hypoperfused zone, was 42.8 +/- 1.3% (n = 10) in the control group and was increased by approximately 100% in cholesterol-fed animals to 83.7 +/- 2.0% (n = 10, p less than .001). To test the hypothesis that vascular obstruction (no reflow) might account for the larger infarct size, thioflavin S was injected immediately before the animals were killed to demarcate perfused myocardium in three additional groups of animals: standard chow-fed rabbits (n = 5), cholesterol-fed rabbits (n = 5), and standard chow-fed rabbits that, in addition, received an infusion of isoproterenol (0.1 microgram/kg/min, n = 6), an intervention believed to increase infarct size through a mechanism not dependent on the no-reflow phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of one-month sacubitril/valsartan treatment in a patient affected by end-stage dystrophinopathic cardiomyopathy

Dystrophinopathic cardiomyopathy (DCM) is an almost constant manifestation in Becker muscular dystrophy (BMD) patients significantly contributing to morbidity and mortality. The nearly complete replacement of the myocardium by fibrous and fatty connective tissue results in an irreversible cardiac failure, characterized by progressive reduction of the ejection fraction. According to PARADIGM-HF trial results, the European Society of Cardiology (ESC) guidelines recommend the use of sacubitril/valsartan in ambulatory patients with heart failure and reduced ejection fraction, who remain symptomatic despite an optimal medical therapy. To date, little is still known about the use of sacubitril/valsartan in DCM. We report the case of a patient with dystrophinopathic end stage dilated cardiomyopathy with reduced ejection fraction who successfully responded to sacubitril/valsartan treatment.Key words: dystrophinopathic cardiomyopathy, heart failure, sacubitril/valsartan, Becker muscular dystrophy